Mutations in Retroviral Genes Associated with Drug · PDF file58 Mutations in Retroviral Genes...
101
58 Mutations in Retroviral Genes Associated with Drug Resistance Shauna A. Clark, 1 Charles Calef, 2 and John W. Mellors 1 1 University of Pittsburgh, Scaife Hall, Suite 818, 3550 Terrace St., Pittsburgh, PA 15261 2 T10, MS K710, Los Alamos National Laboratory, Los Alamos, NM 87545 Introduction Drug resistance is the inevitable consequence of incomplete suppression of HIV replication. The rapid replication rate of HIV and its inherent genetic variation have led to the identification of many HIV variants that exhibit altered drug susceptibility. The growing number of drug resistance mutations listed in this revised table stands as a testimony to the genetic flexibility of HIV. This table, updated in February 2007, lists 947 HIV-1 mutation/drug combinations, of which 37 occur in Gag (including this year, 3 in capsid and 3 in SP-1), 321 in Protease, 9 in Integrase, 374 in RT, and 206 in Env. Although the tables are quite comprehensive, the reader should be reminded that the HIV-1 mutations described are predominantly found in clade B virus and not in other HIV genotypes. Thirty-one mutations in HIV-2 RT and 27 in HIV-2 Protease are listed in the table. In addition, 2 mutations in SIV RT are listed. The column “Selected or Cross-R” describes how the mutations have been identified. “Selected” refers specifically to mutations identified by in vitro passage of virus in increasing concentrations of a compound, or by sequencing isolates from patients on a specific drug therapy. “Cross-R” (cross- resistance) means that virus with a mutation has been shown to have decreased susceptibility to a compound even though selection of the mutation by the compound has not been reported. The “in vitro” column has a “Y” (for yes) when resistance or cross-resistance to the compound is seen using cloned virus or in cell culture studies; the “in vivo” column has a “Y” (for yes) when resistance or cross-resistance to the compound is seen in patients. In the “Amino Acid Change” column a + means amino acids have been inserted into the se- quence, while a ∆ indicates a deletion. In the “Drug Class” column, “NRTI” refers to nucleoside or nucleotide reverse transcriptase inhibitors, while non-nucleoside or HIV-1 specific RT inhibitors are called “NNRTI.” The abbreviation MN stands for “Multiple Nucleoside” and refers to resistance to combinations of NRTIs. “MDR” or multi-drug resistant is noted in the “Compound” column if a muta- tion causes resistance to multiple compounds. Other abbreviations are listed in a separate Abbreviations Table on page 137. All of the information contained in these printed tables and other useful tools are available at our Web site: http://resdb.lanl.gov/Resist_DB. The authors gratefully acknowledge their colleagues for assistance in assembling this table. This work was supported in part by Los Alamos National Laboratory. Contents HIV-1 Gag . . . . . . . . . . . . . . . . . . 59 HIV-1 Capsid . . . . . . . . . . . . . . . . . 61 HIV-1 SP-1 . . . . . . . . . . . . . . . . . . 62 HIV-1 Protease . . . . . . . . . . . . . . . . 63 HIV-2 Protease . . . . . . . . . . . . . . . . 89 HIV-1 RT . . . . . . . . . . . . . . . . . . . 91 HIV-2 RT . . . . . . . . . . . . . . . . . . 111 SIV RT . . . . . . . . . . . . . . . . . . 114 HIV-1 Integrase . . . . . . . . . . . . . . . 115 HIV-1 Envelope . . . . . . . . . . . . . . . 116 Table of Abbreviations . . . . . . . . . . . . 137 Table of Compounds . . . . . . . . . . . . . 137 References . . . . . . . . . . . . . . . . . 143
Transcript of Mutations in Retroviral Genes Associated with Drug · PDF file58 Mutations in Retroviral Genes...
58
Mutations in Retroviral Genes Associated withDrug Resistance
Shauna A. Clark,1 Charles Calef,2 and John W. Mellors1
1 University of Pittsburgh, Scaife Hall, Suite 818, 3550 Terrace St., Pittsburgh, PA 152612 T10, MS K710, Los Alamos National Laboratory, Los Alamos, NM 87545
Introduction
Drug resistance is the inevitable consequence of incomplete suppression of HIV replication. Therapid replication rate of HIV and its inherent genetic variation have led to the identification of manyHIV variants that exhibit altered drug susceptibility. The growing number of drug resistance mutationslisted in this revised table stands as a testimony to the genetic flexibility of HIV. This table, updated inFebruary 2007, lists 947 HIV-1 mutation/drug combinations, of which 37 occur in Gag (including thisyear, 3 in capsid and 3 in SP-1), 321 in Protease, 9 in Integrase, 374 in RT, and 206 in Env. Although thetables are quite comprehensive, the reader should be reminded that the HIV-1 mutations described arepredominantly found in clade B virus and not in other HIV genotypes. Thirty-one mutations in HIV-2RT and 27 in HIV-2 Protease are listed in the table. In addition, 2 mutations in SIV RT are listed.
The column “Selected or Cross-R” describes how the mutations have been identified. “Selected”refers specifically to mutations identified by in vitro passage of virus in increasing concentrations ofa compound, or by sequencing isolates from patients on a specific drug therapy. “Cross-R” (cross-resistance) means that virus with a mutation has been shown to have decreased susceptibility to acompound even though selection of the mutation by the compound has not been reported. The “invitro” column has a “Y” (for yes) when resistance or cross-resistance to the compound is seen usingcloned virus or in cell culture studies; the “in vivo” column has a “Y” (for yes) when resistance orcross-resistance to the compound is seen in patients.
In the “Amino Acid Change” column a + means amino acids have been inserted into the se-quence, while a ∆ indicates a deletion. In the “Drug Class” column, “NRTI” refers to nucleoside ornucleotide reverse transcriptase inhibitors, while non-nucleoside or HIV-1 specific RT inhibitors arecalled “NNRTI.” The abbreviation MN stands for “Multiple Nucleoside” and refers to resistance tocombinations of NRTIs. “MDR” or multi-drug resistant is noted in the “Compound” column if a muta-tion causes resistance to multiple compounds. Other abbreviations are listed in a separate AbbreviationsTable on page 137. All of the information contained in these printed tables and other useful tools areavailable at our Web site: http://resdb.lanl.gov/Resist_DB.
The authors gratefully acknowledge their colleagues for assistance in assembling this table. Thiswork was supported in part by Los Alamos National Laboratory.
Contents
HIV-1 Gag . . . . . . . . . . . . . . . . . . 59
HIV-1 Capsid . . . . . . . . . . . . . . . . . 61
HIV-1 SP-1 . . . . . . . . . . . . . . . . . . 62
HIV-1 Protease . . . . . . . . . . . . . . . . 63
HIV-2 Protease . . . . . . . . . . . . . . . . 89
HIV-1 RT . . . . . . . . . . . . . . . . . . . 91
HIV-2 RT . . . . . . . . . . . . . . . . . . 111
SIV RT . . . . . . . . . . . . . . . . . . 114
HIV-1 Integrase . . . . . . . . . . . . . . . 115
HIV-1 Envelope . . . . . . . . . . . . . . . 116
Table of Abbreviations . . . . . . . . . . . . 137
Table of Compounds . . . . . . . . . . . . . 137
References . . . . . . . . . . . . . . . . . 143
Drug Resistance Mutations in HIV-1 Gag 59
HIV
-1G
ag
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
E12
KPr
otea
seIn
hibi
tor
UIC
-940
03Se
lect
edY
?G
atan
aga0
2
E12
KPr
otea
seIn
hibi
tor
VX
-478
(am
pren
avir
)Se
lect
edY
?G
atan
aga0
2
V35
IPr
otea
seIn
hibi
tor
KN
I-27
2(k
ynos
tatin
)Se
lect
edY
?G
atan
aga0
2
V35
IPr
otea
seIn
hibi
tor
VX
-478
(am
pren
avir
)Se
lect
edY
?G
atan
aga0
2
E40
KPr
otea
seIn
hibi
tor
KN
I-27
2(k
ynos
tatin
)Se
lect
edY
?G
atan
aga0
2
E40
KPr
otea
seIn
hibi
tor
UIC
-940
03Se
lect
edY
?G
atan
aga0
2
L75
RPr
otea
seIn
hibi
tor
VX
-478
(am
pren
avir
)Se
lect
edY
?G
atan
aga0
2
G12
3E
Prot
ease
Inhi
bito
rK
NI-
272
(kyn
osta
tin)
Sele
cted
Y?
Gat
anag
a02
G12
3E
Prot
ease
Inhi
bito
rU
IC-9
4003
Sele
cted
Y?
Gat
anag
a02
Q19
9H
Prot
ease
Inhi
bito
rU
IC-9
4003
Sele
cted
Y?
Gat
anag
a02
H21
9Q
Prot
ease
Inhi
bito
rJE
-214
7Se
lect
edY
?G
atan
aga0
2
H21
9Q
Prot
ease
Inhi
bito
rK
NI-
272
(kyn
osta
tin)
Sele
cted
Y?
Gat
anag
a02
H21
9Q
Prot
ease
Inhi
bito
rU
IC-9
4003
Sele
cted
Y?
Gat
anag
a02
H21
9Q
Prot
ease
Inhi
bito
rV
X-4
78(a
mpr
enav
ir)
Sele
cted
Y?
Gat
anag
a02
G38
1S
Prot
ease
Inhi
bito
rK
NI-
272
(kyn
osta
tin)
Sele
cted
Y?
Gat
anag
a02
V39
0A
Prot
ease
Inhi
bito
rJE
-214
7Se
lect
edY
?G
atan
aga0
2
V39
0D
Prot
ease
Inhi
bito
rV
X-4
78(a
mpr
enav
ir)
Sele
cted
Y?
Gat
anag
a02
R40
9K
Prot
ease
Inhi
bito
rJE
-214
7Se
lect
edY
?G
atan
aga0
2
R40
9K
Prot
ease
Inhi
bito
rK
NI-
272
(kyn
osta
tin)
Sele
cted
Y?
Gat
anag
a02
R40
9K
Prot
ease
Inhi
bito
rU
IC-9
4003
Sele
cted
Y?
Gat
anag
a02
R40
9K
Prot
ease
Inhi
bito
rV
X-4
78(a
mpr
enav
ir)
Sele
cted
Y?
Gat
anag
a02
G41
2D
Prot
ease
Inhi
bito
rU
IC-9
4003
Sele
cted
Y?
Gat
anag
a02
A43
1V
Prot
ease
Inhi
bito
rK
NI-
272
(kyn
osta
tin)
Sele
cted
Y?
Gat
anag
a02
60 Drug Resistance Mutations in HIV-1 Gag
HIV
-1G
ag
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
K43
6E
Prot
ease
Inhi
bito
rR
O03
3–46
49Se
lect
edY
Thi
sPI
did
not
sele
ctre
sist
ance
inth
epr
otea
sege
ne.
Sequ
enci
ngsh
owed
that
mut
atio
nsw
ere
inth
eN
C/p
1cl
eava
gesi
te.
Nijh
uis0
7
I43
7T
Prot
ease
Inhi
bito
rR
O03
3–46
49Se
lect
edY
Thi
sPI
did
not
sele
ctre
sist
ance
inth
epr
otea
sege
ne.
Sequ
enci
ngsh
owed
that
mut
atio
nsw
ere
inth
eN
C/p
1cl
eava
gesi
te.
Nijh
uis0
7
I43
7V
Prot
ease
Inhi
bito
rR
O03
3–46
49Se
lect
edY
Thi
sPI
did
not
sele
ctre
sist
ance
inth
epr
otea
sege
ne.
Sequ
enci
ngsh
owed
that
mut
atio
nsw
ere
inth
eN
C/p
1cl
eava
gesi
te.
Nijh
uis0
7
L44
9F
Prot
ease
Inhi
bito
rJE
-214
7Se
lect
edY
?G
atan
aga0
2
L44
9F
Prot
ease
Inhi
bito
rU
IC-9
4003
Sele
cted
Y?
Gat
anag
a02
L44
9F
Prot
ease
Inhi
bito
rV
X-4
78(a
mpr
enav
ir)
Sele
cted
Y?
Gat
anag
a02
E46
8K
Prot
ease
Inhi
bito
rU
IC-9
4003
Sele
cted
Y?
Gat
anag
a02
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8K
Prot
ease
Inhi
bito
rV
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78(a
mpr
enav
ir)
Sele
cted
Y?
Gat
anag
a02
Drug Resistance Mutations in HIV-1 Capsid (Gag, p24) 61
HIV
-1C
A
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
H22
6Y
Mat
urat
ion
inhi
bito
rPA
-457
(Bev
irim
at)
Sele
cted
YM
utat
ions
foun
dne
arth
eC
term
inus
ofca
psid
Ada
mso
n06
L23
1F
Mat
urat
ion
inhi
bito
rPA
-457
(Bev
irim
at)
Sele
cted
YM
utat
ions
foun
dne
arth
eC
term
inus
ofca
psid
Ada
mso
n06
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1M
Mat
urat
ion
inhi
bito
rPA
-457
(Bev
irim
at)
Sele
cted
YM
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ions
foun
dne
arth
eC
term
inus
ofca
psid
Ada
mso
n06
62 Drug Resistance Mutations in HIV-1 SP-1 (Gag, spacer-1, p2)
HIV
-1SP
1
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
A1
VM
atur
atio
nin
hibi
tor
PA-4
57(B
evir
imat
)Se
lect
edY
Mut
atio
nsfo
und
inSP
-1pe
ptid
eA
dam
son0
6
A3
TM
atur
atio
nin
hibi
tor
PA-4
57(B
evir
imat
)Se
lect
edY
Mut
atio
nsfo
und
inSP
-1pe
ptid
eA
dam
son0
6
A3
VM
atur
atio
nin
hibi
tor
PA-4
57(B
evir
imat
)Se
lect
edY
Mut
atio
nsfo
und
inSP
-1pe
ptid
eA
dam
son0
6
Drug Resistance Mutations in HIV-1 Protease 63
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
T4
PA
CT→
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TPr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)+
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itona
vir)
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cted
?Y
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5
R8
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APr
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hibi
tor
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cted
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tor
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cted
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prov
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plic
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mpe
tenc
yof
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roni
cally
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cted
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roM
.
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tor
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lect
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vitr
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fold
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T91
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fold
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T91
S/V
32I/
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fold
Pass
age
17vi
rus:
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10F/
M46
I/T
91S/
V32
I/I4
7V/V
47A
/G16
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H69
Y:
338
fold
(in
pres
ence
ofp7
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(AN
/F
toV
N/F
)cl
eava
ge-s
item
utat
ion
and
p1/
p6(F
/Lto
F/F)
clea
vage
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atio
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Invi
vo,
susc
eptib
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was
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ced
bym
utat
ions
atpo
sitio
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,54
,10
,63
,71
,84
(4–1
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ld),
K20
M/R
(>20
-fol
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(>40
-fol
d)
Car
rillo
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Kem
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seIn
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tor
AB
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avir
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AB
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itona
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cted
Y?
Sequ
entia
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ulat
ion
ofm
utat
ions
inpa
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pNL
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PV/r
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ears
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ssag
e9,
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FC
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CPr
otea
seIn
hibi
tor
AB
T-53
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itona
vir)
Cro
ss-R
Y?
9-fo
ldre
sist
ant
toJE
-214
7-se
lect
edvi
rus
(L10
F/M
46I/
I47V
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V)
Yos
him
ura9
9
L10
FC
TC→
TT
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otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Cro
ss-R
Y?
21-f
old
resi
sanc
ese
enw
ithlo
pina
vir-
sele
cted
pass
age
17vi
rus:
I84V
/L10
F/M
46I/
T91
S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
L10
FC
TC→
TT
CPr
otea
seIn
hibi
tor
BIL
A21
85B
SSe
lect
edY
?L
10F/
L23
I/V
32I/
M46
I/I4
7V/I
54M
/A71
V/I
84V
:1,
500-
fold
with
asso
ciat
edG
agm
utat
ions
:p1
/p6
clea
vage
site
(Lto
F(C
TT
toT
TT
atP1
′ );p7
/p1
clea
vage
site
(Qto
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AG
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GG
)at
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V(G
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on96
L10
FC
TC→
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otea
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hibi
tor
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zana
vir)
Sele
cted
Y?
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L/L
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M46
I/A
71V
/I84
V/N
88S:
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fold
.L
10Y
,F/I
50L
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P/A
71V
/N88
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-fol
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32I/
M46
I/I8
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89M
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tor
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lect
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mpe
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ory
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64 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
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tro
vivo
Com
men
tsR
efs
L10
FC
TC→
TT
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otea
seIn
hibi
tor
DM
P-32
3Se
lect
edY
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10F/
V82
A:
2-fo
ld;
L10
F/K
45I/
I84V
:50
-fol
dT
isda
le95
,K
ing9
5
L10
FC
TC→
TT
CPr
otea
seIn
hibi
tor
JE-2
147
Sele
cted
Y?
L10
F/I4
7V/I
84V
:19-
fold
.L
10F/
M46
I/I4
7V/
I84V
:28-
fold
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50pa
ssag
esre
quir
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ola-
tion
ofre
sist
ant
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s.
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L10
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otea
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hibi
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ynos
tatin
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ross
-RY
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stan
tto
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147
sele
cted
viru
s(L
10F/
M46
I/I4
7V/I
184V
)Y
oshi
mur
a99
L10
FC
TC→
TT
CPr
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sein
hibi
tor
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-140
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(tip
rana
vir)
Sele
cted
Y?
Aft
er73
pass
ages
9ot
her
mut
atio
nsac
cum
u-
late
dto
give
87fo
ldre
sist
ance
totip
rana
vir
Doy
on05
L10
FC
TC→
TT
CPr
otea
seIn
hibi
tor
SC-5
5389
ASe
lect
edY
?N
88S/
L10
F:25
-fol
dSm
idt9
7
L10
FC
TC→
TT
CPr
otea
seIn
hibi
tor
TM
C11
4(U
IC-9
4017
)C
ross
-RY
?10
-fol
dre
sist
ant
agai
nst
apre
navi
r-se
lect
edm
u-ta
ntL
10F/
V32
I/M
46I/
I54M
/A71
V/I
84V
.73
-fo
ldre
sist
ant
agai
nst
indi
navi
r-se
lect
edL
10F/
L24
I/M
46I/
L63
P/A
71V
/G73
S/V
82T
Koh
03
L10
FC
TC→
TT
CPr
otea
seIn
hibi
tor
UIC
-940
03Se
lect
edY
?in
vitr
ose
lect
ion
inM
T-2
cells
,pa
ssag
e62
Gat
anag
a02
L10
FC
TC→
TT
CPr
otea
seIn
hibi
tor
VB
-11,
328
Sele
cted
Y?
L10
F/I8
4V:
8-fo
ldPa
rtal
edis
95
L10
FC
TC→
TT
CPr
otea
seIn
hibi
tor
VX
-478
(am
pren
avir
)Se
lect
edY
?Se
lect
edfir
stPa
rtal
edis
95
L10
IC
TC→
AT
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
L10
IC
TC→
AT
CPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
Y?
Sele
cted
inin
vitr
opa
ssag
eof
NL
4–3
inC
EM
X17
4ce
llsin
incr
easi
ngco
ncen
trat
ions
ofri
tona
vir.
App
eare
dla
tein
sele
ctio
n(p
as-
sage
44)
Wat
kins
03
L10
IC
TC→
AT
CPr
otea
sein
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
ed?
YM
atsu
oka-
Aiz
awa0
3
L10
IC
TC→
AT
CPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
Con
dra9
6
L10
IC
TC→
AT
CPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+A
BT-
538
(rito
navi
r)+
MK
-639
(ind
inav
ir)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
Drug Resistance Mutations in HIV-1 Protease 65
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
L10
RC
TC→
CG
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
L10
RC
TC→
CG
CPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
L10
R/M
46I/
L63
P/V
82T
:4-
fold
;L
10R
/M46
I/L
63P/
V82
T/I
84V
:8-
fold
Con
dra9
6,C
ondr
a95
L10
VC
TC→
GT
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
L10
VC
TC→
GT
CPr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)+
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Mo0
5
L10
VC
TC→
GT
CPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
Con
dra9
6,C
ondr
a95
L10
VPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
L10
YC
TC→
TAC
Prot
ease
Inhi
bito
rB
MS-
2326
32(a
taza
navi
r)Se
lect
edY
?V
32L
/L33
F/M
46I/
A71
V/I
84V
/N88
S:18
3-fo
ld.
L10
Y,F
/I50
L/L
63P/
A71
V/N
88S:
93-f
old.
V32
I/M
46I/
I84V
/L89
M:
96-f
old.
Gon
g00
I11
VA
TC→
GT
CPr
otea
seIn
hibi
tor
SC-5
2151
(tel
inav
ir)
Sele
cted
Y?
I11V
/M46
I/F5
3L/A
71V
/N88
D:1
0-to
20-f
old
Smid
t97
T12
KA
CA→
AA
APr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)+
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Mo0
5
I13
VA
TA→
GTA
Prot
ease
inhi
bito
rA
BT-
378
(lop
inav
ir)
+
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Mo0
5
I13
VA
TA→
GTA
Prot
ease
inhi
bito
rPN
U-1
4069
0(t
ipra
navi
r)Se
lect
edY
?A
fter
73pa
ssag
es9
othe
rm
utat
ions
accu
mu-
late
dto
give
87fo
ldre
sist
ance
totip
rana
vir
Doy
on05
K14
RA
AG→
AG
GPr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)+
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Mo0
5
I15
VA
TA→
GTA
Prot
ease
Inhi
bito
rPN
U-1
4069
0(t
ipra
navi
r)Se
lect
ed?
YR
usco
ni00
66 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
G16
AG
GG→
GC
GPr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)+
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Mo0
5
G16
EG
GG→
GA
GPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edY
?In
vitr
o,Pa
ssag
e17
viru
sI8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
:re
duce
dsu
scep
tibili
ty33
8fo
ld(i
npr
esen
ceof
p7/p
1(A
N/F
toV
N/F
)cl
eava
ge-s
item
utat
ion
and
p1/p
6(F
/Lto
F/F)
clea
vage
-site
mut
atio
n).
Invi
vo,
susc
eptib
ility
was
redu
ced
4–10
-fol
din
conj
unct
ion
with
mut
atio
nsat
82,
54,
10,
63,
71,
and
84;
>20
-fol
dw
ithK
20M
/Ran
d>
40-
fold
with
F53L
.
Car
rillo
98
G16
EG
GG→
GA
GPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Cro
ss-R
Y?
21-f
old
resi
sanc
ese
enw
ithlo
pina
vir-
sele
cted
pass
age
17vi
rus:
I84V
/L10
F/M
46I/
T91
S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
G16
EG
GG→
GA
GPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
Cro
ss-R
Y?
4-fo
ldre
sisa
nce
seen
with
lopi
navi
r-se
lect
edpa
ssag
e17
viru
s:I8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
K20
IA
AG→
?Pr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YPa
rkin
03
K20
IA
AG→
AT
CPr
otea
sein
hibi
tor
mul
tiple
PISe
lect
ed?
YSv
iche
r05
K20
MA
AG→
AT
GPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
K20
MA
AG→
AT
GPr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YSe
enin
two
patie
nts
follo
win
ga
switc
hfr
omsa
quin
avir.
Ass
ocia
ted
with
redu
ced
susc
epti-
bilit
yto
both
saqu
inav
iran
dne
lfina
vir.
Law
renc
e99
K20
MA
AG→
AT
GPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
Con
dra9
6
K20
MPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
Drug Resistance Mutations in HIV-1 Protease 67
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
K20
RA
AG→
AG
GPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
K20
RA
AG→
AG
GPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
NY
Seco
ndar
ym
utat
ion
occu
rsin
com
bina
tion
with
mut
atio
nsat
V82
,I8
4,M
36,
I54,
and
A71
.
Mol
la96
K20
RA
AG→
AG
GPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
Con
dra9
6
K20
RPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
K20
TA
AG→
AC
GPr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)+
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Mo0
5
K20
TA
AG→
AC
GPr
otea
sein
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
ed?
YA
ssoc
iate
dw
ithL
90M
Svic
her0
5
K20
VPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
A22
VG
CT→
GT
TPr
otea
sein
hibi
tor
mul
tiple
PISe
lect
ed?
YSv
iche
r05
L23
IC
TA→
ATA
Prot
ease
Inhi
bito
rB
ILA
2185
BS
Sele
cted
Y?
L10
F/L
23I/
V32
I/M
46I/
I47V
/I54
M/A
71V
/I84
V:
1,50
0-fo
ldw
ithas
soci
ated
Gag
mut
atio
ns:
p1/
p6cl
eava
gesi
te(L
toF
(CT
Tto
TT
Tat
P1′ );
p7/p
1cl
eava
gesi
te(Q
toR
(CA
Gto
CG
G)
at
P3′ ,
Ato
V(G
CT
toC
TT
)at
P2′ ).
Cro
teau
97,
Doy
on96
L23
IC
TA→
ATA
Prot
ease
inhi
bito
rm
ultip
lePI
Sele
cted
?Y
Mut
atio
nse
lect
edw
hen
eith
erne
lfina
vir
orsa
quin
avir
used
asso
lePI
;al
sose
lect
edin
patie
nts
rece
ivin
gri
tano
vir-
boos
ted
ampr
enav
ir
orsa
quin
avir
John
ston
04
L24
IT
TA→
ATA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
Sele
cted
NY
Inco
njun
ctio
nw
ithot
her
mut
atio
ns,
suce
pti-
bilit
yto
lopi
navi
rw
asre
duce
dby
mut
atio
nsat
posi
tions
82,5
4,10
,63,
71an
d84
by4–
10-f
old,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
L24
IT
TA→
ATA
Prot
ease
Inhi
bito
rA
BT-
538
(rito
navi
r)Se
lect
edY
?Se
lect
edin
invi
tro
pass
age
ofN
L4–
3in
CE
MX
174
cells
inin
crea
sing
conc
entr
atio
ns
ofri
tona
vir.
Wat
kins
03
L24
IT
TA→
ATA
Prot
ease
Inhi
bito
rM
K-6
39(i
ndin
avir
)Se
lect
edN
YC
ondr
a96,
Con
dra9
5
68 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
L24
IT
TA→
ATA
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)+
AB
T-53
8(r
itona
vir)
+M
K-6
39(i
ndin
avir
)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
L24
IT
TA→
ATA
Prot
ease
Inhi
bito
rT
MC
114
(UIC
-940
17)
Cro
ss-R
Y?
73-f
old
resi
stan
tag
ains
tin
dina
vir-
sele
cted
L10
F/L
24I/
M46
I/L
63P/
A71
V/G
73S/
V82
T
Koh
03
D30
NG
AT→
AA
TPr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YD
30N
/A71
V:
7-fo
ld;
D30
Nan
dN
88D
are
mos
tco
mm
onin
vivo
afte
r24
wee
ksof
ther
-ap
y;th
eydo
not
caus
ecr
oss-
resi
stan
ceto
othe
r
prot
ease
inhi
bito
rs
Patic
k98
D30
NPr
otea
seIn
hibi
tor
TM
C-1
14C
ross
-RY
Aut
hors
use
high
reso
ultio
ncr
ysta
llogr
aphy
tode
term
ine
the
mol
ecul
arba
sis
for
inhi
bito
nby
TM
C-1
14
Kov
alev
sky0
6
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rA
-770
03Se
lect
edY
?V
32I
appe
ars
first
;oc
curs
with
R8Q
orV
82I/
M46
L
Kap
lan9
4
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
Sele
cted
Y?
I84V
/L10
F/M
46I/
T91
S/V
32I/
I47V
:46
fold
Pass
age
17vi
rus:
I84V
/L10
F/M
46I/
T91
S/V
32I/
I47V
/V47
A/G
16E
/H69
Y:
338
fold
(in
pres
ence
ofp7
/p1
(AN
/Fto
VN
/F)
clea
vage
-si
tem
utat
ion
and
p1/p
6(F
/Lto
F/F)
clea
vage
-
site
mut
atio
n).
Car
rillo
98
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
+
AB
T-53
8(r
itona
vir)
Sele
cted
Y?
Sequ
entia
lac
cum
ulat
ion
ofm
utat
ions
inpa
s-sa
geof
pNL
4–3
inM
T4
cells
inpr
esen
ceof
aL
PV/r
itona
vir
ratio
nof
5:1.
App
ears
four
thin
sequ
ence
,in
pass
age
11,
afte
rI8
4V,
L10
Fan
d
M46
I,an
dfo
llow
edby
I47V
,Q
58E
.
Mo0
3
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rB
ILA
1906
BS
Sele
cted
Y?
Dom
inan
tpo
pula
tion
atpa
ssag
e33
:V
32I/
M46
I/A
71V
/I84
A:
520-
fold
resi
stan
t.A
ssoc
i-at
edG
agm
utat
ions
:p1
/p6
clea
vage
site
(Lto
F(C
TT
toT
TT
atP1
′ )
Cro
teau
97
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rB
ILA
2185
BS
Sele
cted
Y?
L10
F/L
23I/
V32
I/M
46I/
I47V
/I54
M/A
71V
/I84
V:
1,50
0-fo
ldw
ithas
soci
ated
Gag
mut
atio
ns:
p1/
p6cl
eava
gesi
te(L
toF
(CT
Tto
TT
Tat
P1′ );
p7/p
1cl
eava
gesi
te(Q
toR
(CA
Gto
CG
G)
at
P3′ ,
Ato
V(G
CT
toC
TT
)at
P2′ ).
Cro
teau
97,
Doy
on96
Drug Resistance Mutations in HIV-1 Protease 69
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rB
MS-
2326
32(a
taza
navi
r)Se
lect
edY
?V
32L
/L33
F/M
46I/
A71
V/I
84V
/N88
S:18
3-fo
ld.
L10
Y,F
/I50
L/L
63P/
A71
V/N
88S:
93-f
old.
V32
I/M
46I/
I84V
/L89
M:
96-f
old.
Gon
g00
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rJE
-214
7Se
lect
edY
?in
vitr
ose
lect
ion
inM
T-2
cells
,pa
ssag
e33
Gat
anag
a02
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rK
NI-
272
(kyn
osta
tin)
Sele
cted
YN
invi
tro
sele
ctio
nin
MT-
2ce
lls,
pass
age
27G
atan
aga0
2,G
ulni
k95
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rM
K-6
39(i
ndin
avir
)Se
lect
edY
YV
32I/
M46
L/V
82A
:3-
fold
;V
32I/
M46
L/A
71V
/V
82A
:14
-fol
dC
ondr
a96,
Con
dra9
5
V32
IG
TA→
ATA
Prot
ease
inhi
bito
rPN
U-1
4069
0(t
ipra
navi
r)Se
lect
edY
?A
fter
73pa
ssag
es9
othe
rm
utat
ions
accu
mu-
late
dto
give
87fo
ldre
sist
ance
totip
rana
vir
Doy
on05
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)C
ross
-RY
?4-
fold
resi
sanc
ese
enw
ithlo
pina
vir-
sele
cted
pass
age
17vi
rus:
I84V
/L10
F/M
46I/
T91
S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rT
MC
114
(UIC
-940
17)
Cro
ss-R
Y?
10-f
old
resi
stan
tag
ains
tap
rena
vir-
sele
cted
mu-
tant
L10
F/V
32I/
M46
I/I5
4M/A
71V
/I84
V.
Koh
03
V32
IG
TA→
ATA
Prot
ease
Inhi
bito
rV
X-4
78(a
mpr
enav
ir)
Sele
cted
Y?
invi
tro
sele
ctio
nin
MT-
2ce
lls,
pass
age
10G
atan
aga0
2
L33
FT
TA→
TT
CPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
NY
Seco
ndar
ym
utat
ion
occu
rsin
com
bina
tion
with
mut
atio
nsat
V82
,I8
4,M
36,
I54,
and
A71
.
Mol
la96
L33
FT
TA→
TT
CPr
otea
seIn
hibi
tor
BM
S-23
2632
(ata
zana
vir)
Sele
cted
Y?
V32
L/L
33F/
M46
I/A
71V
/I84
V/N
88S:
183-
fold
.L
10Y
,F/I
50L
/L63
P/A
71V
/N88
S:93
-fol
d.V
32I/
M46
I/I8
4V/L
89M
:96
-fol
d.
Gon
g00
L33
FT
TA→
TT
TPr
otea
sein
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
Y?
Aft
er73
pass
ages
9ot
her
mut
atio
nsac
cum
u-
late
dto
give
87fo
ldre
sist
ance
totip
rana
vir
Doy
on05
L33
IT
TA→
ATA
Prot
ease
Inhi
bito
rA
G-1
343
(nel
finav
ir)
Sele
cted
NY
Ass
ocia
ted
with
Cla
deE
viru
sA
riyo
shi0
3
E34
QG
AA→
CA
APr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YA
ssoc
iate
dw
ithei
ther
L33
For
F53L
Svic
her0
5
E34
QG
AA→
CA
APr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edY
?Se
lect
edby
pass
age
24in
anIn
vitr
opa
ssag
eof
pNL
4–3
inM
T4
cells
inth
epr
esen
ceof
lopi
navi
r.G
enom
eal
read
yha
dI5
0V,
M46
I,L
10F
and
I47V
from
prev
ious
pass
ages
.M
u-ta
tion
was
seen
inco
mbi
natio
nw
ithV
32I,
Q61
Han
dE
65Q
.
Mo0
3
E35
DG
AA→
?Pr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
?Y
Seen
in60
%of
patie
nts
rece
ivin
gtip
rana
vir
ther
apy.
Rus
coni
00
70 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
E35
GG
AA→
GG
APr
otea
sein
hibi
tor
mul
tiple
PISe
lect
ed?
YSv
iche
r05
E35
GPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
M36
IA
TG→
ATA
Prot
ease
Inhi
bito
rA
BT-
538
(rito
navi
r)Se
lect
edN
YIn
vivo
,V
82oc
curs
first
,of
ten
follo
wed
by
chan
ges
at54
,71
and
36
Mol
la96
M36
IA
TG→
ATA
Prot
ease
Inhi
bito
rA
G-1
343
(nel
finav
ir)
Sele
cted
NY
D30
N/M
36I/
L63
P:60
-fol
d,al
thou
ghL
63P
may
bea
poly
mor
phis
m.
Patic
k98
M36
IA
TG→
ATA
Prot
ease
inhi
bito
rPN
U-1
4069
0(t
ipra
navi
r)Se
lect
edY
?A
fter
73pa
ssag
es9
othe
rm
utat
ions
accu
mu-
late
dto
give
87fo
ldre
sist
ance
totip
rana
vir
Doy
on05
M36
LA
TG→
CT
GPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
NY
Invi
vo,
V82
occu
rsfir
st,
ofte
nfo
llow
edby
chan
ges
at54
,71
and
36
Mol
la96
M36
VA
TG→
GT
GPr
otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Res
ch05
N37
DPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
?Y
Seen
in30
%of
patie
nts
rece
ivin
gtip
rana
vir
ther
apy.
Rus
coni
00
S37
DA
GT→
GA
TPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
The
seno
nac
tive
site
mut
atio
nsar
eas
soci
ated
with
low
erbi
ndin
gaf
finity
ofth
ein
hibi
tors
topr
otea
sein
enzy
mat
icas
says
Prot
ease
cont
ain-
ing
thes
em
utat
ions
wer
eas
saye
d:L
10I/
M36
I/S3
7D/M
46I/
R57
K/L
63P/
A71
V/G
73S/
L90
M/
I93L
Muz
amm
il03,
Ols
en99
R41
KA
GA→
AA
APr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
?Y
Seen
in20
%of
patie
nts
rece
ivin
gtip
rana
vir
ther
apy.
Rus
coni
00
R41
TA
GA→
AC
APr
otea
sein
hibi
tor
TM
C11
4(U
IC-9
4017
)Se
lect
edY
?C
ontr
ary
tose
lect
ion
data
,SD
Mw
ere
test
edag
ains
tT
MC
114
and
susc
eptib
ility
was
incr
ease
d
DeM
eyer
05
K43
TA
AA→
AC
APr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YA
ssoc
iate
dw
ithei
ther
I54A
orw
ithm
ulti
PIre
sist
ance
mut
atio
nsV
82A
,V
32I,
and
I47V
Svic
her0
5
K43
TPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
K45
IA
AA→
ATA
Prot
ease
Inhi
bito
rD
MP-
323
Sele
cted
Y?
L10
F/K
45I/
I84V
:50
-fol
dT
isda
le95
,K
ing9
5
K45
IA
AA→
ATA
Prot
ease
inhi
bito
rPN
U-1
4069
0(t
ipra
navi
r)Se
lect
edY
?A
fter
73pa
ssag
es9
othe
rm
utat
ions
accu
mu-
late
dto
give
87fo
ldre
sist
ance
totip
rana
vir
Doy
on05
K45
RA
AA→
AG
APr
otea
sein
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
ed?
YA
ssoc
iate
dw
ithD
30N
and
N88
DSv
iche
r05
Drug Resistance Mutations in HIV-1 Protease 71
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
M46
FA
TG→
TT
CPr
otea
seIn
hibi
tor
A-7
7003
Sele
cted
Y?
Sele
cted
inch
roni
cally
infe
cted
cells
at1
mic
roM
Kap
lan9
4
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rA
-770
03Se
lect
edY
?N
oef
fect
onsu
scep
tibili
tybu
tim
prov
esre
pli-
catio
nco
mpe
tenc
yof
R8Q
mut
ant;
R8K
/M46
I/
G48
V:
20-f
old
Ho9
4,K
apla
n94
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
Sele
cted
Y?
Acq
uire
din
conj
unct
ion
with
M46
Iof
invi
tro
pass
age
ofpN
L4–
3in
MT
4ce
lls,
pass
age
7
Mo0
3
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
Sele
cted
Y?
I84V
/L10
F/M
46I:
4fo
ldI8
4V/L
10F/
M46
I/T
91S:
12fo
ldI8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V:
46fo
ldPa
ssag
e17
viru
s:I8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
:33
8fo
ld(i
npr
esen
ceof
p7/p
1(A
N/F
toV
N/F
)cl
eava
ge-s
item
utat
ion
and
p1/p
6(F
/Lto
F/F)
clea
vage
-site
mut
atio
n).
Car
rillo
98
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
+
AB
T-53
8(r
itona
vir)
Sele
cted
Y?
Acq
uire
din
conj
unct
ion
with
I50V
inpa
s-sa
ge8
(pN
L4–
3in
MT
4ce
lls,
in1:
5lo
pina
vir/
rito
navi
r)
Mo0
3
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
+
AB
T-53
8(r
itona
vir)
Sele
cted
Y?
Sequ
entia
lac
cum
ulat
ion
ofm
utat
ions
inpa
s-sa
geof
pNL
4–3
inM
T4
cells
inpr
esen
ceof
aL
PV/r
itona
vir
ratio
nof
5:1.
App
ears
thir
din
sequ
ence
,in
pass
age
9to
11,
afte
rI8
4Van
d
L10
F,an
dfo
llow
edby
V32
I,I4
7V,
Q58
E.
Mo0
3
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rA
BT-
538
(rito
navi
r)Se
lect
edY
YIn
vitr
o,oc
curs
afte
rse
lect
ion
ofI8
4V.
Invi
vo,
V82
A/F
/T/S
occu
rsfir
st,
follo
wed
bych
ange
s
at54
,71
and
36
Mar
kow
itz95
,M
olla
96
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rA
G-1
343
(nel
finav
ir)
Sele
cted
YY
5-fo
ldre
sist
ance
inco
mbi
natio
nw
ithI8
4V;
ofte
nse
enw
ithD
30N
invi
voPa
tick9
6,Pa
tick9
8
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rB
ILA
1906
BS
Sele
cted
Y?
Dom
inan
tpo
pula
tion
atpa
ssag
e33
:V
32I/
M46
I/A
71V
/I84
A:
520-
fold
resi
stan
t.A
ssoc
i-at
edG
agm
utat
ions
:p1
/p6
clea
vage
site
(Lto
F(C
TT
toT
TT
atP1
′ )
Cro
teau
97,
Doy
on96
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rB
ILA
2185
BS
Sele
cted
Y?
L10
F/L
23I/
V32
I/M
46I/
I47V
/I54
M/A
71V
/I84
V:
1,50
0-fo
ldw
ithas
soci
ated
Gag
mut
atio
ns:
p1/
p6cl
eava
gesi
te(L
toF
(CT
Tto
TT
Tat
P1′ );
p7/p
1cl
eava
gesi
te(Q
toR
(CA
Gto
CG
G)
at
P3′ ,
Ato
V(G
CT
toC
TT
)at
P2′ ).
Cro
teau
97,
Doy
on96
72 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rB
MS-
2326
32(a
taza
navi
r)Se
lect
edY
?V
32L
/L33
F/M
46I/
A71
V/I
84V
/N88
S:18
3-fo
ld.
L10
Y,F
/I50
L/L
63P/
A71
V/N
88S:
93-f
old.
V32
I/M
46I/
I84V
/L89
M:
96-f
old.
Gon
g00
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rD
MP
450
Y?
Prob
ably
com
pens
ator
yH
odge
96
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rJE
-214
7Se
lect
edY
?L
10F/
M46
I/I4
7V/I
84V
:28-
fold
.>
50pa
ssag
es
requ
ired
for
isol
atio
nof
resi
stan
tvi
rus.
Yos
him
ura9
9
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rK
NI-
272
(kyn
osta
tin)
Sele
cted
Y?
invi
tro
sele
ctio
nin
MT-
2ce
lls,
pass
age
27G
atan
aga0
2
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rM
K-6
39(i
ndin
avir
)Se
lect
edN
YM
46I/
L63
P/V
82T
:4-
fold
;L
10R
/M46
I/L
63P/
V82
T:
4-fo
ld;
L10
R/M
46I/
L63
P/V
82T
/I84
V:
8-fo
ld
Con
dra9
6,C
ondr
a95
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)C
ross
-RY
?4-
fold
resi
sanc
ese
enw
ithlo
pina
vir-
sele
cted
pass
age
17vi
rus:
I84V
/L10
F/M
46I/
T91
S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
M46
IA
TG→
CT
GPr
otea
seIn
hibi
tor
SC-5
2151
(tel
inav
ir)
Sele
cted
Y?
I11V
/M46
I/F5
3L/A
71V
/N88
D:1
0-to
20-f
old
Smid
t97
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rT
MC
114
(UIC
-940
17)
Cro
ss-R
Y?
10-f
old
resi
stan
tag
ains
tap
rena
vir-
sele
cted
mu-
tant
L10
F/V
32I/
M46
I/I5
4M/A
71V
/I84
V.
73-
fold
resi
stan
tag
ains
tin
dina
vir-
sele
cted
L10
F/
L24
I/M
46I/
L63
P/A
71V
/G73
S/V
82T
Koh
03
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rU
IC-9
4003
Sele
cted
Y?
invi
tro
sele
ctio
nin
MT-
2ce
lls,
pass
age
62G
atan
aga0
2
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rV
B-1
1,32
8Se
lect
edY
?I5
0V/M
46I/
I47V
:20
-fol
dPa
rtal
edis
95
M46
IA
TG→
ATA
Prot
ease
Inhi
bito
rV
X-4
78(a
mpr
enav
ir)
Sele
cted
Y?
Aro
seat
late
rpa
ssag
es;
L10
F/I8
4Val
read
y
pres
ent
Part
aled
is95
M46
LA
TG→
TT
CPr
otea
seIn
hibi
tor
A-7
7003
Sele
cted
Y?
Kap
lan9
4
M46
LA
TG→
TT
GPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
M46
LA
TG→
TT
GPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
Y?
Sele
cted
inin
vitr
opa
ssag
eof
NL
4–3
inC
EM
X17
4ce
llsin
incr
easi
ngco
ncen
trat
ions
ofri
tona
vir.
App
eare
dea
rly
inse
lect
ion.
Wat
kins
03
M46
LA
TG→
CT
GPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
YY
Seco
ndar
ym
utat
ion
occu
rsin
com
bina
tion
with
mut
atio
nsat
V82
,I8
4,M
36,
I54,
and
A71
.
Mol
la96
Drug Resistance Mutations in HIV-1 Protease 73
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
M46
LA
TG→
TT
GPr
otea
seIn
hibi
tor
BIL
A19
06B
SSe
lect
edY
?D
omin
ant
popu
latio
nat
pass
age
33:
M46
L/
A71
V/I
84A
:52
0-fo
ldre
sist
ant.
Ass
ocia
ted
Gag
mut
atio
ns:
p1/p
6cl
eava
gesi
te(L
toF
(CT
Tto
TT
Tat
P1′ )
Cro
teau
97,
Doy
on96
M46
LA
TG→
CT
GPr
otea
seIn
hibi
tor
DM
P-32
3Se
lect
edY
?V
82A
/M46
L:
7-fo
ld;
V82
A/M
46L
/L97
V:
11-
fold
Kin
g95
M46
LA
TG→
TT
GPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
YY
App
ears
seco
ndin
sequ
ence
.C
ombi
natio
n
V82
A/M
46L
/V32
I/A
71V
:14
-fol
d
Tis
dale
95
M46
LPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
M46
LA
TG→
TT
GPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+A
BT-
538
(rito
navi
r)+
MK
-639
(ind
inav
ir)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
M46
LA
TG→
TT
GPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+A
BT-
538
(rito
navi
r)+
MK
-639
(ind
inav
ir)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
M46
LA
TG→
CT
GPr
otea
seIn
hibi
tor
VX
-478
(am
pren
avir
)Se
lect
edY
?In
com
bina
tion
with
I50V
Tis
dale
95
I47
AA
TA→
GC
APr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edY
YC
ause
shy
pers
usce
ptib
ility
tosa
quin
avir
Car
illo9
8
I47
AA
TA→
GC
APr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)+
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Mo0
5
I47
VA
TA→
GTA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
Sele
cted
Y?
I84V
/L10
F/M
46I/
T91
S/V
32I/
I47V
:46
fold
Pass
age
17vi
rus:
I84V
/L10
F/M
46I/
T91
S/V
32I/
I47V
/V47
A/G
16E
/H69
Y:
338
fold
(in
pres
ence
ofp7
/p1
(AN
/Fto
VN
/F)
clea
vage
-si
tem
utat
ion
and
p1/p
6(F
/Lto
F/F)
clea
vage
-
site
mut
atio
n).
Car
rillo
98
I47
VA
TA→
GTA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
+
AB
T-53
8(r
itona
vir)
Sele
cted
Y?
Sequ
entia
lac
cum
ulat
ion
ofm
utat
ions
inpa
s-sa
geof
pNL
4–3
inM
T4
cells
inpr
esen
ceof
aL
PV/r
itona
vir
ratio
nof
5:1.
App
ears
fifth
inse
quen
ce,
inpa
ssag
e17
,af
ter
I84V
,L
10F,
M46
Ian
dV
32I,
and
follo
wed
byQ
58E
.
Mo0
3
74 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
I47
VA
TA→
GTA
Prot
ease
Inhi
bito
rA
BT-
538
(rito
navi
r)C
ross
-RY
?21
-fol
dre
sisa
nce
seen
with
lopi
navi
r-se
lect
edpa
ssag
e17
viru
s:I8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
I47
VA
TA→
CTA
Prot
ease
Inhi
bito
rB
ILA
2185
BS
Sele
cted
Y?
L10
F/L
23I/
V32
I/M
46I/
I47V
/I54
M/A
71V
/I84
V:
1,50
0-fo
ldw
ithas
soci
ated
Gag
mut
atio
ns:
p1/
p6cl
eava
gesi
te(L
toF
(CT
Tto
TT
Tat
P1′ );
p7/p
1cl
eava
gesi
te(Q
toR
(CA
Gto
CG
G)
at
P3′ ,
Ato
V(G
CT
toC
TT
)at
P2′ ).
Cro
teau
97,
Doy
on96
I47
VA
TA→
CTA
Prot
ease
Inhi
bito
rJE
-214
7Se
lect
edY
?L
10F/
I47V
/I84
V:1
9-fo
ld.
L10
F/M
46I/
I47V
/I8
4V:2
8-fo
ld.
>50
pass
ages
requ
ired
for
isol
a-
tion
ofre
sist
ant
viru
s.
Yos
him
ura9
9
I47
VA
TA→
CTA
Prot
ease
Inhi
bito
rK
NI-
272
(kyn
osta
tin)
Cro
ss-R
Y?
7-fo
ldre
sist
ant
toJE
-214
7se
lect
edvi
rus
(L10
F/M
46I/
I47V
/I18
4V)
Yos
him
ura9
9
I47
VPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
I47
VA
TA→
GTA
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)C
ross
-RY
?4-
fold
resi
sanc
ese
enw
ithlo
pina
vir-
sele
cted
pass
age
17vi
rus:
I84V
/L10
F/M
46I/
T91
S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
I47
VA
TA→
CTA
Prot
ease
Inhi
bito
rV
B-1
1,32
8Se
lect
edY
?I5
0V/M
46I/
I47V
:20
-fol
dPa
rtal
edis
95
I47
VA
TA→
CTA
Prot
ease
Inhi
bito
rV
X-4
78(a
mpr
enav
ir)
Sele
cted
Y?
Aro
seat
late
rpa
ssag
es;
L10
F/I8
4Val
read
y
pres
ent
Part
aled
is95
G48
MPr
otea
seIn
hibi
tor
P-19
46C
ross
-RY
Cau
sed
28fo
ldre
duce
dsu
scpe
tibili
tyin
con-
junc
tion
with
mut
atio
nsat
82,
90,
53,
and
54
Sevi
gny0
6
G48
VG
GG→
GT
GPr
otea
seIn
hibi
tor
A-7
7003
Sele
cted
YN
R8K
/M46
I/G
48V
:20
-fol
d;G
48V
/I82
T:
100-
fold
Bor
man
96
G48
VG
GG→
GT
GPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
?Y
Vas
udev
acha
ri96
G48
VG
GG→
GT
GPr
otea
seIn
hibi
tor
MP-
134
Cro
ss-R
Y?
MP-
167-
sele
cted
viru
sco
nfer
s5-
fold
incr
ease
inIC
90M
o96
G48
VG
GG→
GT
GPr
otea
seIn
hibi
tor
MP-
167
Sele
cted
Y?
L10
F/G
48V
:20
-fol
dM
o96
G48
VG
GG→
GT
GPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
Sele
cted
YY
G48
V/L
90M
:>
100-
fold
enzy
me
resi
stan
ce;
G48
V/L
90M
/I54
V:
>50
-fol
d(s
ubty
peB
or
O).
Invi
vo,
also
had
V82
A
Jaco
bsen
95,
Ebe
rle9
5,W
inte
rs98
a
Drug Resistance Mutations in HIV-1 Protease 75
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
G48
VG
GG→
GT
GPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+A
BT-
538
(rito
navi
r)+
MK
-639
(ind
inav
ir)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
G48
VG
GG→
GT
GPr
otea
seIn
hibi
tor
SC-5
2151
(tel
inav
ir)
Cro
ss-R
Y?
MP-
167-
sele
cted
viru
sco
nfer
s16
-fol
din
crea
sein
IC90
Mo9
6
I50
LA
TT→
CT
TPr
otea
seIn
hibi
tor
BM
S-23
2632
(ata
zana
vir)
Sele
cted
YY
Gon
g00,
Col
onno
04
I50
LA
TT→
CT
TPr
otea
seIn
hibi
tor
BM
S-23
2632
(ata
zana
vir)
Sele
cted
Y?
V32
L/L
33F/
M46
I/A
71V
/I84
V/N
88S:
183-
fold
.L
10Y
,F/I
50L
/L63
P/A
71V
/N88
S:93
-fol
d.V
32I/
M46
I/I8
4V/L
89M
:96
-fol
d.
Gon
g00
I50
VA
TT→
GT
TPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edY
?A
cqui
red
inco
njun
ctio
nw
ithM
46I
ofin
vitr
o
pass
age
ofpN
L4–
3in
MT
4ce
lls,
pass
age
7
Mo0
3
I50
VA
TT→
GT
TPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)+
AB
T-53
8(r
itona
vir)
Sele
cted
Y?
Acq
uire
din
conj
unct
ion
with
M46
Iin
pas-
sage
8(p
NL
4–3
inM
T4
cells
,in
1:5
lopi
navi
r/
rito
navi
r)
Mo0
3
I50
VPr
otea
seIn
hibi
tor
TM
C-1
14C
ross
-RY
Aut
hors
use
high
reso
ultio
ncr
ysta
llogr
aphy
tode
term
ine
the
mol
ecul
arba
sis
for
inhi
bito
nby
TM
C-1
15
Kov
alev
sky0
6
I50
VA
TT→
GT
TPr
otea
seIn
hibi
tor
UIC
-940
03Se
lect
edY
?in
vitr
ose
lect
ion
inM
T-2
cells
,pa
ssag
e62
Gat
anag
a02
I50
VA
TT→
GT
TPr
otea
seIn
hibi
tor
VB
-11,
328
Sele
cted
Y?
I50V
/M46
I/I4
7V:
20-f
old
Part
aled
is95
I50
VA
TT→
GT
TPr
otea
seIn
hibi
tor
VX
-478
(am
pren
avir
)Se
lect
edY
?R
epla
ced
I84V
Part
aled
is95
F53
LT
TT→
?Pr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
F53
LPr
otea
seIn
hibi
tor
P-19
46C
ross
-RY
Cau
sed
28fo
ldre
duce
dsu
scpe
tibili
tyin
con-
junc
tion
with
mut
atio
nsat
48,8
2,90
,an
d54
Sevi
gny0
6
F53
LT
TT→
?Pr
otea
seIn
hibi
tor
SC-5
2151
(tel
inav
ir)
Sele
cted
Y?
I11V
/M46
I/F5
3L/A
71V
/N88
D:1
0-to
20-f
old
Smid
t97
76 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
F53
YT
TT→
TAT
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)+
AB
T-53
8(r
itona
vir)
+M
K-6
39(i
ndin
avir
)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
I54
AA
TC→
GC
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YPa
rkin
03
I54
APr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
I54
LA
TC→
CT
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
I54
LA
TT→
CT
TPr
otea
seIn
hibi
tor
VX
-478
(am
pren
avir
)Se
lect
edY
YM
agui
re02
I54
MA
TC→
AT
GPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YPa
rkin
03
I54
MA
TT→
AT
GPr
otea
seIn
hibi
tor
BIL
A21
85B
SSe
lect
edY
?L
10F/
L23
I/V
32I/
M46
I/I4
7V/I
54M
/A71
V/I
84V
:1,
500-
fold
with
asso
ciat
edG
agm
utat
ions
:p1
/p6
clea
vage
site
(Lto
F(C
TT
toT
TT
atP1
′ );p7
/p1
clea
vage
site
(Qto
R(C
AG
toC
GG
)at
P3′ ,
Ato
V(G
CT
toC
TT
)at
P2′ ).
Cro
teau
97,
Doy
on96
I54
MPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
I54
MA
TT→
AT
GPr
otea
seIn
hibi
tor
TM
C11
4(U
IC-9
4017
)C
ross
-RY
?10
-fol
dre
sist
ant
agai
nst
apre
navi
r-se
lect
edm
u-
tant
L10
F/V
32I/
M46
I/I5
4M/A
71V
/I84
V.
Koh
03
I54
MA
TC→
AT
GPr
otea
seIn
hibi
tor
VX
-478
(am
pren
avir
)Se
lect
edY
?in
vitr
ose
lect
ion
inM
T-2
cells
,pa
ssag
e31
Gat
anag
a02
I54
SA
TC→
AG
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YPa
rkin
03
I54
TA
TC→
AC
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
Drug Resistance Mutations in HIV-1 Protease 77
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
I54
VA
TC→
GT
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
I54
VA
TC→
GT
CPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
NY
Invi
vo,
V82
A/F
/T/S
occu
rsfir
st,
follo
wed
by
chan
ges
at54
,71
and
36
Mol
la96
I54
VPr
otea
seIn
hibi
tor
P-19
46C
ross
-RY
Cau
sed
28fo
ldre
duce
dsu
scpe
tibili
tyin
con-
junc
tion
with
mut
atio
nsat
48,
82,
90,
53,
and
54
Sevi
gny0
6
I54
VA
TC→
GT
CPr
otea
sein
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
Y?
Aft
er73
pass
ages
9ot
her
mut
atio
nsac
cum
u-
late
dto
give
87fo
ldre
sist
ance
totip
rana
vir
Doy
on05
I54
VA
TA→
GTA
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)Se
lect
edY
?In
subt
ype
Oan
dB
Ebe
rle9
5
I54
VA
TA→
GTA
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)+
AB
T-53
8(r
itona
vir)
+M
K-6
39(i
ndin
avir
)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
K55
RA
AA→
AG
APr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YA
ssoc
iate
dw
ithV
82A
,I5
4V,
and
M46
ISv
iche
r05
K55
RA
AA→
AG
APr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YSe
enin
one
patie
ntfo
llow
ing
asw
itch
from
saqu
inav
ir.A
ssoc
iate
dw
ithre
duce
dsu
scep
ti-
bilit
yto
both
saqu
inav
iran
dne
lfina
vir.
Law
renc
e99
R57
KA
GA→
AA
APr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YSe
enin
one
patie
ntfo
llow
ing
asw
itch
from
saqu
inav
ir.A
ssoc
iate
dw
ithre
duce
dsu
scep
ti-
bilit
yto
both
saqu
inav
iran
dne
lfina
vir.
Law
renc
e99
Q58
EPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)+
AB
T-53
8(r
itona
vir)
Sele
cted
Y?
Sequ
entia
lac
cum
ulat
ion
ofm
utat
ions
inpa
s-sa
geof
pNL
4–3
inM
T4
cells
inpr
esen
ceof
aL
PV/r
itona
vir
ratio
nof
5:1.
App
ears
last
inse
-qu
ence
,in
pass
age
17,
afte
rI8
4V,
L10
F,M
46I,
V32
I,an
dI4
7V.
Mo0
3
Q58
EPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
D60
EG
AT→
GA
APr
otea
seIn
hibi
tor
DM
P45
0Se
lect
edY
?Pr
obab
lyco
mpe
nsat
ory
Hod
ge96
78 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
D60
EG
AT→
GA
APr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
?Y
Seen
in30
%of
patie
nts
rece
ivin
gtip
rana
vir
ther
apy.
Rus
coni
00
Q61
HC
AG→
?Pr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edY
?Se
lect
edby
pass
age
24in
anIn
vitr
opa
ssag
eof
pNL
4–3
inM
T4
cells
inth
epr
esen
ceof
lopi
navi
r.G
enom
eal
read
yha
dI5
0V,
M46
I,L
10F
and
I47V
from
prev
ious
pass
ages
.M
u-ta
tion
was
seen
inco
mbi
natio
nw
ithV
32I,
E34
Q,
and
E65
Q.
Mo0
3
L63
AC
TC→
GC
CPr
otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Res
ch05
L63
CC
TC→
TG
CPr
otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Res
ch05
L63
PC
TC→
CC
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
L63
PC
TC→
CC
CPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
Y?
Sele
cted
inin
vitr
opa
ssag
eof
NL
4–3
inC
EM
X17
4ce
llsin
incr
easi
ngco
ncen
trat
ions
ofri
tona
vir.
App
eare
dea
rly
inse
lect
ion.
Wat
kins
03
L63
PC
TC→
CC
CPr
otea
seIn
hibi
tor
BM
S-23
2632
(ata
zana
vir)
Sele
cted
Y?
V32
L/L
33F/
M46
I/A
71V
/I84
V/N
88S:
183-
fold
.L
10Y
,F/I
50L
/L63
P/A
71V
/N88
S:93
-fol
d.V
32I/
M46
I/I8
4V/L
89M
:96
-fol
d.
Gon
g00
L63
PC
TC→
CC
CPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
M46
I/L
63P/
V82
T:
4-fo
ld;
L10
R/M
46I/
L63
P/V
82T
/I84
V:
8-fo
ld;
L10
R/M
46I/
L63
P/V
82T
:4-
fold
Con
dra9
6,C
ondr
a95
L63
PC
TC→
CC
CPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
Sele
cted
Y?
Sele
cted
bypa
ssag
e27
ofin
vitr
opa
ssag
eof
NL
4–3
inC
EM
X17
4ce
llsin
incr
easi
ngco
n-
cent
ratio
nsof
indi
navi
r.
Wat
kins
03
L63
PC
TC→
CC
CPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+A
BT-
538
(rito
navi
r)+
MK
-639
(ind
inav
ir)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
L63
PC
TC→
CC
CPr
otea
seIn
hibi
tor
TM
C11
4(U
IC-9
4017
)C
ross
-RY
?73
-fol
dre
sist
ant
agai
nst
indi
navi
r-se
lect
ed
L10
F/L
24I/
M46
I/L
63P/
A71
V/G
73S/
V82
T
Koh
03
Drug Resistance Mutations in HIV-1 Protease 79
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
L63
QC
TC→
CA
GPr
otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Res
ch05
L63
SC
TC→
TC
CPr
otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Res
ch05
L63
TC
TC→
AC
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YPa
rkin
03
I64
VA
TA→
GTA
Prot
ease
inhi
bito
rA
BT-
378
(lop
inav
ir)
+
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Mo0
5
E65
QG
AA→
CA
APr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edY
?Se
lect
edby
pass
age
24in
anIn
vitr
opa
ssag
eof
pNL
4–3
inM
T4
cells
inth
epr
esen
ceof
lopi
navi
r.G
enom
eal
read
yha
dI5
0V,
M46
I,L
10F
and
I47V
from
prev
ious
pass
ages
.M
u-ta
tion
was
seen
inco
mbi
natio
nw
ithV
32I,
E34
Q,
and
Q61
H.
Mo0
3
I66
FA
TC→
TT
CPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+A
BT-
538
(rito
navi
r)+
MK
-639
(ind
inav
ir)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
H69
KPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
H69
YC
AT→
TAT
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
Sele
cted
Y?
Pass
age
17vi
rus:
I84V
/L10
F/M
46I/
T91
S/V
32I/
I47V
/V47
A/G
16E
/H69
Y:
338
fold
(in
pres
ence
ofp7
/p1
(AN
/Fto
VN
/F)
clea
vage
-si
tem
utat
ion
and
p1/p
6(F
/Lto
F/F)
clea
vage
-
site
mut
atio
n).
Car
rillo
98
H69
YC
AT→
TAT
Prot
ease
Inhi
bito
rA
BT-
538
(rito
navi
r)C
ross
-RY
?21
-fol
dre
sisa
nce
seen
with
lopi
navi
r-se
lect
edpa
ssag
e17
viru
s:I8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
H69
YC
AT→
TAT
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)C
ross
-RY
?4-
fold
resi
sanc
ese
enw
ithlo
pina
vir-
sele
cted
pass
age
17vi
rus:
I84V
/L10
F/M
46I/
T91
S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
K70
EA
AA→
GA
APr
otea
sein
hibi
tor
TM
C11
4(U
IC-9
4017
)Se
lect
edY
?D
eMey
er05
80 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
A71
IG
CT→
AT
TPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
A71
LG
CT→
CT
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
A71
TG
CT→
AC
TPr
otea
seIn
hibi
tor
A-7
7003
Cro
ss-R
Y?
BM
S-18
6318
-sel
ecte
dvi
rus
A71
T/V
82A
:4-
fold
Patic
k95
A71
TG
CT→
AC
TPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
A71
TG
CT→
AC
TPr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YPa
tick9
8
A71
TG
CT→
AC
TPr
otea
seIn
hibi
tor
BM
S-18
6318
Sele
cted
Y?
A71
T/V
82A
:15
-fol
dPa
tick9
5
A71
TG
CT→
AC
TPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
Con
dra9
6,C
ondr
a95
A71
TG
CT→
AC
TPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
?Y
Rus
coni
00
A71
VG
CT→
GT
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
YY
Occ
urre
dby
pass
age
22in
vitr
opr
eced
edby
I84V
,M
46I
and
V82
F.In
vivo
,V
82A
/F/T
/Soc
curs
first
,fo
llow
edby
chan
ges
at54
,71
and
36
Mar
kow
itz95
,M
olla
96
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YD
30N
/A71
V:
7-fo
ld;
M46
I/L
63P/
A71
V/I
84V
:30
-fol
dPa
tick9
8
Drug Resistance Mutations in HIV-1 Protease 81
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
BIL
A19
06B
SSe
lect
edY
?D
omin
ant
popu
latio
nat
pass
age
33:
V32
I/M
46I/
A71
V/I
84A
orM
46L
/A71
V/I
84A
:52
0-fo
ldre
sist
ant.
Ass
ocia
ted
Gag
mut
atio
ns:
p1/
p6cl
eava
gesi
te(L
toF
(CT
Tto
TT
Tat
P1′ )
Cro
teau
97,
Doy
on96
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
BIL
A21
85B
SSe
lect
edY
?L
10F/
L23
I/V
32I/
M46
I/I4
7V/I
54M
/A71
V/I
84V
:1,
500-
fold
with
asso
ciat
edG
agm
utat
ions
:p1
/p6
clea
vage
site
(Lto
F(C
TT
toT
TT
atP1
′ );p7
/p1
clea
vage
site
(Qto
R(C
AG
toC
GG
)at
P3′ ,
Ato
V(G
CT
toC
TT
)at
P2′ ).
Cro
teau
97,
Doy
on96
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
BM
S-23
2632
(ata
zana
vir)
Sele
cted
Y?
V32
L/L
33F/
M46
I/A
71V
/I84
V/N
88S:
183-
fold
.L
10Y
,F/I
50L
/L63
P/A
71V
/N88
S:93
-fol
d.V
32I/
M46
I/I8
4V/L
89M
:96
-fol
d.
Gon
g00
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
KN
I-27
2(k
ynos
tatin
)Se
lect
edY
Nin
vitr
ose
lect
ion
inM
T-2
cells
,pa
ssag
e27
,in
30%
ofcl
ones
Gat
anag
a02,
Gul
nik9
5
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
YY
App
ears
four
thin
sequ
ence
.C
ombi
natio
n
V82
A/M
46L
/V32
I/A
71V
:14
-fol
d
Tis
dale
95
A71
VG
CT→
GT
TPr
otea
sein
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
Y?
Aft
er73
pass
ages
9ot
her
mut
atio
nsac
cum
u-
late
dto
give
87fo
ldre
sist
ance
totip
rana
vir
Doy
on05
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
Sele
cted
Y?
Sele
cted
inin
vitr
opa
ssag
eof
NL
4–3
inC
EM
X17
4ce
llsin
incr
easi
ngco
ncen
trat
ions
ofsa
quin
avir.
Thi
sm
utat
ion
appe
ared
inea
rly
inpa
ssag
ean
dw
asm
aint
aine
dun
tilth
eap
-
pear
ance
ofV
77I.
Wat
kins
03
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+A
BT-
538
(rito
navi
r)+
MK
-639
(ind
inav
ir)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
SC-5
2151
(tel
inav
ir)
Sele
cted
Y?
I11V
/M46
I/F5
3L/A
71V
/N88
D:1
0-to
20-f
old
Smid
t97
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
TM
C11
4(U
IC-9
4017
)C
ross
-RY
?10
-fol
dre
sist
ant
agai
nst
apre
navi
r-se
lect
edm
u-ta
ntL
10F/
V32
I/M
46I/
I54M
/A71
V/I
84V
.73
-fo
ldre
sist
ant
agai
nst
indi
navi
r-se
lect
edL
10F/
L24
I/M
46I/
L63
P/A
71V
/G73
S/V
82T
Koh
03
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
UIC
-940
03Se
lect
edY
?in
vitr
ose
lect
ion
inM
T-2
cells
,pa
ssag
e62
Gat
anag
a02
82 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
A71
VG
CT→
GT
TPr
otea
seIn
hibi
tor
VX
-478
(am
pren
avir
)Se
lect
edY
?in
vitr
ose
lect
ion
inM
T-2
cells
,pa
ssag
e31
Gat
anag
a02
G73
SG
GT→
AG
TPr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YSe
enin
two
patie
nts
follo
win
ga
switc
hfr
omsa
quin
avir.
Ass
ocia
ted
with
redu
ced
susc
epti-
bilit
yto
both
saqu
inav
iran
dne
lfina
vir.
Law
renc
e99
G73
SG
GT→
GC
TPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
Em
erge
sfo
llow
ing
asw
itch
from
saqu
inav
irto
indi
navi
r.
Dul
ious
t99
G73
SG
GT→
GC
TPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
Sele
cted
Y?
Sele
cted
bypa
ssag
e18
ofin
vitr
opa
ssag
eof
NL
4–3
inC
EM
X17
4ce
llsin
incr
easi
ngco
n-
cent
ratio
nsof
indi
navi
r.
Wat
kins
03
G73
SG
GT→
GC
TPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+A
BT-
538
(rito
navi
r)+
MK
-639
(ind
inav
ir)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
G73
SG
GT→
GC
TPr
otea
seIn
hibi
tor
TM
C11
4(U
IC-9
4017
)C
ross
-RY
?73
-fol
dre
sist
ant
agai
nst
indi
navi
r-se
lect
ed
L10
F/L
24I/
M46
I/L
63P/
A71
V/G
73S/
V82
T
Koh
03
T74
PPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
T74
SA
CA→
TC
APr
otea
sein
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
ed?
YSv
iche
r05
L76
VT
TA→
GTA
Prot
ease
inhi
bito
rA
BT-
378
(lop
inav
ir)
+
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Mo0
5
V77
IG
TA→
ATA
Prot
ease
Inhi
bito
rA
G-1
343
(nel
finav
ir)
Sele
cted
NY
Patic
k98
V77
IG
TA→
ATA
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)Se
lect
edY
?Se
lect
edin
invi
tro
pass
age
ofN
L4–
3in
CE
MX
174
cells
inin
crea
sing
conc
entr
atio
nsof
saqu
inav
ir.T
his
mut
atio
nap
pear
edla
tein
the
pass
age
and
corr
elat
edw
itha
reve
rsio
nof
A71
V.
Wat
kins
03
V77
IG
TA→
ATA
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)+
AB
T-53
8(r
itona
vir)
+M
K-6
39(i
ndin
avir
)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
Drug Resistance Mutations in HIV-1 Protease 83
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
V82
AG
TC→
GC
CPr
otea
seIn
hibi
tor
A-7
7003
Sele
cted
Y?
Rar
e;se
enw
ithM
46F;
V32
Iap
pear
sfir
st;
pro-
gres
sion
toV
32I/
M46
Van
dV
32I/
/M46
V/
A71
V/V
82A
occu
rsev
enin
the
abse
nce
ofdr
ug
Bor
man
96
V82
AG
TC→
GC
CPr
otea
seIn
hibi
tor
A-7
7003
Cro
ss-R
Y?
BM
S-18
6318
-sel
ecte
dvi
rus
A71
T/V
82A
:4-
fold
Patic
k95
V82
AG
TC→
GC
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
V82
AG
TC→
GC
CPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
NY
Invi
vo,
V82
occu
rsfir
st,
ofte
nfo
llow
edby
chan
ges
atI5
4,A
71an
dM
36.
Mol
la96
V82
AG
TC→
GC
CPr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YL
awre
nce9
9
V82
AG
TC→
GC
CPr
otea
seIn
hibi
tor
BM
S-18
6318
Sele
cted
Y?
A71
T/V
82A
:15
-fol
dPa
tick9
5
V82
AG
TC→
GC
CPr
otea
seIn
hibi
tor
DM
P-32
3Se
lect
edY
?V
82A
/M46
L:
7-fo
ld;
V82
A/M
46L
/L97
V:
11-
fold
Kin
g95
V82
AG
TC→
GC
CPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
YY
V32
I/M
46L
/V82
A:
3-fo
ld;
V32
I/M
46L
/A71
V/
V82
A:
14-f
old
Con
dra9
6,C
ondr
a95
V82
APr
otea
seIn
hibi
tor
P-19
46C
ross
-RY
Cau
sed
28fo
ldre
duce
dsu
scpe
tibili
tyin
con-
junc
tion
with
mut
atio
nsat
48,
90,
53,
and
54
Sevi
gny0
6
V82
AG
TC→
GC
CPr
otea
seIn
hibi
tor
P994
1Se
lect
edY
?U
sed
plaq
ueas
say
and
endp
oint
titra
tion
to
sele
ctm
utan
t.
Otto
93
V82
AG
TC→
GC
CPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
Sele
cted
NY
Follo
ws
G48
Vdu
ring
saqu
inav
irth
erap
yor
afte
ra
switc
hto
nelfi
navi
ror
indi
navi
r.
Win
ters
98a
V82
FG
TC→
TT
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
V82
FG
TC→
TT
CPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
YY
Invi
vo,
V82
occu
rsfir
st,
ofte
nfo
llow
edby
chan
ges
atI5
4,A
71an
dM
36.
Mol
ecul
arcl
one
ofV
82F
alon
e:4–
5-fo
ldre
sist
ant
invi
tro.
Mar
kow
itz95
,M
olla
96
V82
FG
TC→
TT
CPr
otea
seIn
hibi
tor
DM
P-32
3Se
lect
edY
?V
82F/
I84V
:97
-fol
dK
ing9
5
84 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
V82
IG
TC→
AT
CPr
otea
seIn
hibi
tor
A-7
7003
Sele
cted
Y?
No
resi
stan
ceal
one
but
V32
Ian
dV
82I
are
syne
rgis
ticm
utat
ions
yiel
ding
20-f
old
enzy
me
resi
stan
ce.
Kap
lan9
4
V82
IG
TC→
AT
CPr
otea
seIn
hibi
tor
JE-2
147
Sele
cted
Y?
invi
tro
sele
ctio
nin
MT-
2ce
lls,
pass
age
33G
atan
aga0
2
V82
IG
TC→
AT
CPr
otea
seIn
hibi
tor
KN
I-27
2(k
ynos
tatin
)Se
lect
edY
?in
vitr
ose
lect
ion
inM
T-2
cells
,pa
ssag
e27
Gat
anag
a02
V82
LG
TC→
CT
CPr
otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Res
ch05
V82
LG
TC→
CT
CPr
otea
sein
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
Y?
Aft
er73
pass
ages
9ot
her
mut
atio
nsac
cum
u-
late
dto
give
87fo
ldre
sist
ance
totip
rana
vir
Doy
on05
V82
MG
TC→
AT
GPr
otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Res
ch05
V82
SG
TC→
TC
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YPa
rkin
03
V82
SG
TC→
TC
CPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
NY
V82
Sor
Toc
curs
afte
rV
82A
orF.
Mol
la96
V82
TG
TC→
AC
CPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
V82
TG
TC→
AC
CPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
NY
V82
Sor
Toc
curs
afte
rV
82A
orF.
Mol
la96
V82
TG
TC→
AC
CPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
M46
I/L
63P/
V82
T:
4-fo
ld;
L10
R/M
46I/
L63
P/V
82T
:4-
fold
;L
10R
/M46
I/L
63P/
V82
T/I
84V
:8-
fold
Con
dra9
6,C
ondr
a95
V82
TPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
V82
TG
TC→
AC
CPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+A
BT-
538
(rito
navi
r)+
MK
-639
(ind
inav
ir)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
V82
TG
TC→
AC
CPr
otea
seIn
hibi
tor
TM
C11
4(U
IC-9
4017
)C
ross
-RY
?73
-fol
dre
sist
ant
agai
nst
indi
navi
r-se
lect
ed
L10
F/L
24I/
M46
I/L
63P/
A71
V/G
73S/
V82
T
Koh
03
N83
DPr
otea
seIn
hibi
tor
PNU
-140
690
(tip
rana
vir)
Sele
cted
YB
axte
r06
Drug Resistance Mutations in HIV-1 Protease 85
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
I84
AA
TA→
GC
APr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edY
?4-
fold
resi
stan
cew
hen
inco
mbi
natio
nw
ithV
32I
Patic
k96
I84
AA
TA→
GC
APr
otea
seIn
hibi
tor
BIL
A19
06B
SSe
lect
edY
?D
omin
ant
popu
latio
nat
pass
age
33:
V32
I/M
46I/
A71
V/I
84A
orM
46L
/A71
V/I
84A
:52
0-fo
ldre
sist
ant.
Ass
ocia
ted
Gag
mut
atio
ns:
p1/
p6cl
eava
gesi
te(L
toF
(CT
Tto
TT
Tat
P1′ )
Cro
teau
97,
Doy
on96
I84
AA
TA→
GC
APr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
Y?
Sele
cted
inin
vitr
opa
ssag
eof
NL
4–3
inC
EM
X17
4ce
llsin
incr
easi
ngco
ncen
trat
ions
ofin
dina
vir.
Thi
sm
utat
ion
appe
ared
inco
n-
junc
tion
with
M46
I,I5
4V,
L63
Pan
dA
71V
.
Wat
kins
03
I84
AA
TA→
GC
APr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+A
BT-
538
(rito
navi
r)+
MK
-639
(ind
inav
ir)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
Sele
cted
Y?
I84V
/L10
F/M
46I:
4fo
ldI8
4V/L
10F/
M46
I/T
91S:
12fo
ldI8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V:
46fo
ldPa
ssag
e17
viru
s:I8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
:33
8fo
ld(i
npr
esen
ceof
p7/p
1(A
N/F
toV
N/F
)cl
eava
ge-s
item
utat
ion
and
p1/p
6(F
/Lto
F/F)
clea
vage
-site
mut
atio
n).
Car
rillo
98
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rA
BT-
378
(lop
inav
ir)
+
AB
T-53
8(r
itona
vir)
Sele
cted
Y?
Sequ
entia
lac
cum
ulat
ion
ofm
utat
ions
inpa
s-sa
geof
pNL
4–3
inM
T4
cells
inpr
esen
ceof
aL
PV/r
itona
vir
ratio
nof
5:1.
App
ears
first
inse
quen
ce,
inpa
ssag
e6,
follo
wed
byL
10F,
M46
I,V
32I,
I47V
,Q
58E
.
Mo0
3
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rA
BT-
538
(rito
navi
r)Se
lect
edY
?Se
lect
edin
invi
tro
pass
age
ofN
L4–
3in
CE
MX
174
cells
inin
crea
sing
conc
entr
atio
nsof
rito
navi
r.A
ppea
red
late
inse
lect
ion
(pas
-
sage
34)
Wat
kins
03
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rA
BT-
538
(rito
navi
r)Se
lect
edY
YFi
rst
mut
atio
nse
enin
invi
tro
pass
age.
Mol
ec-
ular
clon
e8–
10-f
old
resi
stan
t.
Mar
kow
itz95
,M
olla
96
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rA
G-1
343
(nel
finav
ir)
Sele
cted
Y?
M46
I/L
63P/
A71
V/I
84V
:30
-fol
dPa
tick9
6
86 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rB
ILA
2185
BS
Sele
cted
Y?
L10
F/L
23I/
V32
I/M
46I/
I47V
/I54
M/A
71V
/I84
V:
1,50
0-fo
ldw
ithas
soci
ated
Gag
mut
atio
ns:
p1/
p6cl
eava
gesi
te(L
toF
(CT
Tto
TT
Tat
P1′ );
p7/p
1cl
eava
gesi
te(Q
toR
(CA
Gto
CG
G)
at
P3′ ,
Ato
V(G
CT
toC
TT
)at
P2′ ).
Cro
teau
97,
Doy
on96
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rB
MS-
2326
32(a
taza
navi
r)Se
lect
edY
?V
32L
/L33
F/M
46I/
A71
V/I
84V
/N88
S:18
3-fo
ld.
L10
Y,F
/I50
L/L
63P/
A71
V/N
88S:
93-f
old.
V32
I/M
46I/
I84V
/L89
M:
96-f
old.
Gon
g00
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rD
MP
450
Sele
cted
Y?
Hod
ge96
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rD
MP-
323
Sele
cted
Y?
Occ
urs
with
K45
I/L
10F
and
V82
F;M
olec
ular
clon
eof
I84V
alon
e:50
-fol
dT
isda
le95
,K
ing9
5
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rJE
-214
7Se
lect
edY
?L
10F/
I47V
/I84
V:1
9-fo
ld.
L10
F/M
46I/
I47V
/I8
4V:2
8-fo
ld.
>50
pass
ages
requ
ired
for
isol
a-
tion
ofre
sist
ant
viru
s.
Yos
him
ura9
9
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rK
NI-
272
(kyn
osta
tin)
Sele
cted
YN
invi
tro
sele
ctio
nin
MT-
2ce
lls,
pass
age
27G
atan
aga0
2,G
ulni
k95
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rM
K-6
39(i
ndin
avir
)Se
lect
edN
YG
48V
/I84
V/L
90M
:30
-fol
d;L
10R
/M46
I/L
63P/
V82
T/I
84V
:8-
fold
Con
dra9
6,C
ondr
a95
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rM
P-13
4Se
lect
edY
?M
o96
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rM
P-16
7C
ross
-RY
?M
P-13
4-se
lect
edvi
rus
conf
ers
5-fo
ldin
crea
sein
IC90
Mo9
6
I84
VA
TA→
GTA
Prot
ease
inhi
bito
rPN
U-1
4069
0(t
ipra
navi
r)Se
lect
edY
?A
fter
73pa
ssag
es9
othe
rm
utat
ions
accu
mu-
late
dto
give
87fo
ldre
sist
ance
totip
rana
vir
Doy
on05
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)Se
lect
edY
?In
com
bina
tion
with
G48
Van
dL
90M
:30
-fol
dT
isda
le95
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rR
o31
–895
9(s
aqui
navi
r)+
AB
T-53
8(r
itona
vir)
+M
K-6
39(i
ndin
avir
)
Sele
cted
Y?
NL
4–3
pass
aged
inC
EM
X17
4in
pres
ence
ofSQ
V+
RT
V+
IDV
.Se
lect
edm
utan
tha
dot
her
PIm
utat
ions
.U
sed
8-m
utan
tcl
one
for
susc
epti-
bilit
yas
says
:L
10I,
I54V
,L
63P,
A71
V,
V82
T,
I84V
,M
90L
.
Wat
kins
03
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rR
PI-3
12Se
lect
edY
?el
-Far
rash
94
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rSC
-521
51(t
elin
avir
)C
ross
-RY
?M
P-13
4-se
lect
edvi
rus
conf
ers
8-fo
ldin
crea
sein
IC90
Mo9
6
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rT
MC
114
(UIC
-940
17)
Cro
ss-R
Y?
10-f
old
resi
stan
tag
ains
tap
rena
vir-
sele
cted
mu-
tant
L10
F/V
32I/
M46
I/I5
4M/A
71V
/I84
V.
Koh
03
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rV
B-1
1,32
8Se
lect
edY
?L
10F/
I84V
:8-
fold
Part
aled
is95
Drug Resistance Mutations in HIV-1 Protease 87
HIV
-1P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
I84
VA
TA→
GTA
Prot
ease
Inhi
bito
rV
X-4
78(a
mpr
enav
ir)
Sele
cted
Y?
Inco
mbi
natio
nw
ithL
10F
Part
aled
is95
I85
VA
TT→
GT
TPr
otea
sein
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
?Y
Svic
her0
5
N88
DA
AT→
GA
TPr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YD
30N
and
N88
Dar
em
ost
com
mon
invi
voaf
ter
24w
eeks
ofth
erap
y;th
eydo
not
caus
e
cros
s-re
sist
ance
toot
her
prot
ease
inhi
bito
rs.
Patic
k98
N88
DA
AT→
GA
TPr
otea
seIn
hibi
tor
SC-5
2151
(tel
inav
ir)
Sele
cted
Y?
N88
Dco
mpe
nsat
ory,
nore
sist
ance
alon
eSm
idt9
7
N88
GA
AT→
GG
TPr
otea
sein
hibi
tor
AB
T-37
8(l
opin
avir
)+
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Mo0
5
N88
SA
AT→
AG
TPr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YPa
tick9
8
N88
SA
AT→
AG
TPr
otea
seIn
hibi
tor
BM
S-23
2632
(ata
zana
vir)
Sele
cted
Y?
V32
L/L
33F/
M46
I/A
71V
/I84
V/N
88S:
183-
fold
.L
10Y
,F/I
50L
/L63
P/A
71V
/N88
S:93
-fol
d.V
32I/
M46
I/I8
4V/L
89M
:96
-fol
d.
Gon
g00
N88
SA
AT→
AG
TPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Cro
ss-R
Y?
SC-5
5389
A-s
elec
ted
mut
ant
conf
ers
3-fo
ldre
sist
ance
Smid
t97
N88
SA
AT→
AG
TPr
otea
seIn
hibi
tor
SC-5
5389
ASe
lect
edY
?Su
ffici
ent
toco
nfer
resi
stan
ceal
one
(19-
fold
),bu
t25
-fol
din
com
bina
tion
with
L10
FSm
idt9
7
L89
MT
TG→
AT
GPr
otea
seIn
hibi
tor
BM
S-23
2632
(ata
zana
vir)
Sele
cted
Y?
V32
L/L
33F/
M46
I/A
71V
/I84
V/N
88S:
183-
fold
.L
10Y
,F/I
50L
/L63
P/A
71V
/N88
S:93
-fol
d.V
32I/
M46
I/I8
4V/L
89M
:96
-fol
d.
Gon
g00
L90
MT
TG→
AT
GPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edN
YIn
conj
unct
ion
with
othe
rm
utat
ions
,su
cept
i-bi
lity
tolo
pina
vir
was
redu
ced
bym
utat
ions
atpo
sitio
ns82
,54,
10,6
3,71
and
84by
4–10
-fol
d,
K20
M/R
by>
20-f
old
and
F53L
by>
40-f
old.
Kem
pf01
L90
MT
TG→
AT
GPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
NY
Seco
ndar
ym
utat
ion
occu
rsin
com
bina
tion
with
mut
atio
nsat
V82
,I8
4,M
36,
I54,
and
A71
.
Mol
la96
L90
MT
TG→
AT
GPr
otea
seIn
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
edN
YR
are
inpa
tient
sin
Patic
kst
udy;
mor
eco
mm
on
inL
awre
nce
stud
y
Patic
k98,
Law
renc
e99
L90
MT
TG→
AT
GPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
Con
dra9
6
L90
MPr
otea
seIn
hibi
tor
P-19
46C
ross
-RY
Cau
sed
28fo
ldre
duce
dsu
scpe
tibili
tyin
con-
junc
tion
with
mut
atio
nsat
48,8
2,53
,an
d54
Sevi
gny0
6
88 Drug Resistance Mutations in HIV-1 Protease
HIV
-1P
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ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
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tro
vivo
Com
men
tsR
efs
L90
MT
TG→
AT
GPr
otea
seIn
hibi
tor
Ro
31–8
959
(saq
uina
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Sele
cted
YY
G48
V/L
90M
:>
100-
fold
enzy
me
resi
stan
ce;
doub
lem
utan
tra
rein
vivo
;L
90M
mos
tco
m-
mon
invi
vo.
Jaco
bsen
95,
Ebe
rle9
5,W
inte
rs98
a
L90
MPr
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seIn
hibi
tor
TM
C-1
14C
ross
-RY
Aut
hors
use
high
reso
ultio
ncr
ysta
llogr
aphy
tode
term
ine
the
mol
ecul
arba
sis
for
inhi
bito
nby
TM
C-1
16
Kov
alev
sky0
6
T91
SA
CT→
TC
TPr
otea
seIn
hibi
tor
AB
T-37
8(l
opin
avir
)Se
lect
edY
?I8
4V/L
10F/
M46
I/T
91S:
12fo
ldI8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V:
46fo
ldPa
ssag
e17
viru
s:I8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V/
V47
A/G
16E
/H69
Y:
338
fold
(in
pres
ence
ofp7
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(AN
/Fto
VN
/F)
clea
vage
-site
mut
atio
n
and
p1/p
6(F
/Lto
F/F)
clea
vage
-site
mut
atio
n.
Car
rillo
98
T91
SA
CT→
TC
TPr
otea
seIn
hibi
tor
AB
T-53
8(r
itona
vir)
Cro
ss-R
Y?
21-f
old
resi
sanc
ese
enw
ithlo
pina
vir-
sele
cted
pass
age
17vi
rus:
I84V
/L10
F/M
46I/
T91
S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
T91
SA
CT→
TC
TPr
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seIn
hibi
tor
Ro
31–8
959
(saq
uina
vir)
Sele
cted
Y?
4-fo
ldre
sisa
nce
seen
with
lopi
navi
r-se
lect
edpa
ssag
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viru
s:I8
4V/L
10F/
M46
I/T
91S/
V32
I/I4
7V/V
47A
/G16
E/H
69Y
Car
rillo
98
Q92
KC
AG→
AA
GPr
otea
sein
hibi
tor
mul
tiple
PISe
lect
ed?
YSv
iche
r05
I93
LA
TT→
CT
TPr
otea
seIn
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
NY
Muz
amm
il03,
Ols
en99
C95
FT
GC→
TT
CPr
otea
sein
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+M
K-6
39(i
ndin
avir
)
Sele
cted
?Y
Ass
ocia
ted
with
L90
Man
dI9
3LSv
iche
r05
L97
VT
TA→
GTA
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ease
Inhi
bito
rD
MP-
323
Sele
cted
Y?
No
resi
stan
ceal
one;
V82
A/M
46L
/L97
V:
11-
fold
Kin
g95
Drug Resistance Mutations in HIV-2 Protease 89
HIV
-2P
rote
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
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tro
vivo
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men
tsR
efs
K7
NA
AA→
AA
TPr
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sein
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
?Y
Dam
ond0
5
V10
IG
TC→
AT
CPr
otea
sein
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
?Y
Dam
ond0
5
V22
IG
TT→
AT
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sein
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
ed?
YD
amon
d05
A34
EG
CA→
GA
APr
otea
sein
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
?Y
Dam
ond0
5
A34
SG
CA→
TC
APr
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sein
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
?Y
Dam
ond0
5
I36
VA
TT→
GT
TPr
otea
sein
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
?Y
Dam
ond0
5
L38
FT
TG→
TT
TPr
otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Dam
ond0
5
I46
TA
TT→
AC
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otea
sein
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
?Y
Dam
ond0
5
I46
VA
TT→
GT
TPr
otea
sein
hibi
tor
Ro
31–8
959
(saq
uina
vir)
Sele
cted
?Y
Dam
ond0
5
G48
RG
GG→
CG
GPr
otea
sein
hibi
tor
Ro
31–8
959
(saq
uina
vir)
Sele
cted
?Y
Dam
ond0
5
I54
LA
TC→
CT
CPr
otea
sein
hibi
tor
Ro
31–8
959
(saq
uina
vir)
+M
K-6
39(i
ndin
avir
)
Sele
cted
?Y
Dam
ond0
5
G55
RG
GG→
CG
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otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
Sele
cted
?Y
Dam
ond0
5
V62
AG
TT→
GC
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otea
sein
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
ed?
YD
amon
d05
E63
AG
AG→
GC
GPr
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sein
hibi
tor
MK
-639
(ind
inav
ir)
Sele
cted
?Y
Dam
ond0
5
E63
QG
AG→
CA
GPr
otea
sein
hibi
tor
Ro
31–8
959
(saq
uina
vir)
Sele
cted
?Y
Dam
ond0
5
T74
NA
CA→
AA
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otea
sein
hibi
tor
AG
-134
3(n
elfin
avir
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lect
ed?
YD
amon
d05
T77
IA
CT→
AT
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sein
hibi
tor
MK
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(ind
inav
ir)
Sele
cted
?Y
Dam
ond0
5
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EG
GA→
GA
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sein
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
ed?
YD
amon
d05
T80
YA
CA→
TAT
Prot
ease
inhi
bito
rM
K-6
39(i
ndin
avir
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lect
ed?
YD
amon
d05
I82
FA
TT→
TT
TPr
otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
+M
K-6
39(i
ndin
avir
)Se
lect
ed?
YD
amon
d05
I82
MA
TT→
AT
GPr
otea
sein
hibi
tor
MK
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(ind
inav
ir)
Sele
cted
?Y
Dam
ond0
5
I84
LA
TA→
TTA
Prot
ease
inhi
bito
rM
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39(i
ndin
avir
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lect
ed?
YD
amon
d05
I84
VA
TA→
GTA
Prot
ease
inhi
bito
rM
K-6
39(i
ndin
avir
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lect
ed?
YD
amon
d05
90 Drug Resistance Mutations in HIV-2 Protease
HIV
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Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
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nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
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tro
vivo
Com
men
tsR
efs
F85
LT
TT→
TTA
Prot
ease
inhi
bito
rM
K-6
39(i
ndin
avir
)Se
lect
ed?
YD
amon
d05
R87
KA
GA→
AA
APr
otea
sein
hibi
tor
AG
-134
3(n
elfin
avir
)Se
lect
ed?
YD
amon
d05
L90
MT
TG→
AT
GPr
otea
sein
hibi
tor
AB
T-53
8(r
itona
vir)
+M
K-6
39(i
ndin
avir
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lect
ed?
YD
amon
d05
M95
IA
TG→
AT
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otea
sein
hibi
tor
MK
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(ind
inav
ir)
Sele
cted
?Y
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ond0
5
Drug Resistance Mutations in HIV-1 RT 91
HIV
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T
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ino
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lect
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nge
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nge
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V35
IN
ucle
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tor
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cted
YIn
crea
sed
NR
TI
susc
eptib
ility
Svic
her0
6
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ucle
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cted
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Nuc
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Inhi
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r(N
RT
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(zid
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cted
?Y
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215Y
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–70-
fold
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ld.
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der8
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arde
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2974
7Se
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edY
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tor
VR
X-4
1363
8Se
lect
edY
Zha
ng06
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ucle
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eR
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hibi
tor
(NR
TI)
Sele
cted
YSv
iche
r06
K43
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ucle
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hibi
tor
(NR
TI)
Sele
cted
YSv
iche
r06
E44
AG
AA→
GC
AN
ucle
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TIn
hibi
tor
(NR
TI)
3TC
(lam
ivud
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Cro
ss-R
NY
Con
fers
mod
erat
ere
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ance
inab
senc
eof
M18
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mut
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aybe
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mot
edby
thym
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2
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DG
AA→
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ucle
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tor
(NR
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ss-R
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Con
fers
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erat
ele
vels
ofre
sist
ance
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C(7
–32-
fold
)w
hen
pres
ent
inan
AZ
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ant
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ound
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W/2
15Y
)
Her
togs
00
I50
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ucle
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tor
(NR
TI)
Sele
cted
YIn
crea
sed
NR
TI
susc
eptib
ility
Svic
her0
6
P52
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CT→
CG
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ucle
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hibi
tor
(NR
TI)
d4T
(sta
vudi
ne)
Sele
cted
Y?
Sele
ctio
nof
resi
stan
tH
IV-1
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ssag
edin
MT-
4ce
lls
Gas
hnik
ova0
3
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DA
AT→
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ucle
osid
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tor
(NR
TI)
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(sta
vudi
ne)
Sele
cted
Y?
Sele
ctio
nof
resi
stan
tH
IV-1
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ssag
edin
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hnik
ova0
3
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hibi
tor
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2974
7Se
lect
edY
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ng06
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hibi
tor
VR
X-4
1363
8Se
lect
edY
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ng06
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CC→
GT
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ultip
leN
ucle
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DR
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ti-dr
ug
resi
stan
t)
Sele
cted
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Val
one
has
noef
fect
,bu
tin
com
bina
-tio
nw
ithm
utat
ions
at75
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6,15
1ca
uses
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tiN
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.
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hibi
tor
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2974
7Se
lect
edY
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ng06
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hibi
tor
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X-4
1363
8Se
lect
edY
Zha
ng06
K65
RA
AA→
AG
AN
ucle
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hibi
tor
(NR
TI)
1592
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(aba
cavi
r)Se
lect
edY
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65R
/L74
V:
3.6-
fold
;K
65R
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4V:
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ld;
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74V
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4V:
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-fol
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le97
K65
RA
AA→
AG
AN
ucle
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hibi
tor
(NR
TI)
3TC
(lam
ivud
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Cro
ss-R
Y?
>3-
fold
resi
stan
ceB
azm
i00
K65
RA
AA→
AG
AN
ucle
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hibi
tor
(NR
TI)
BC
H-1
0652
(+/-
dOT
C)
Sele
cted
Y?
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R/M
184V
:4.
2-fo
ld.
Tayl
or00
K65
RA
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AG
AN
RT
Icy
clo-
d4G
Cro
ss-R
Y?
4fo
ldre
sist
ance
Ray
05
K65
RA
AA→
AG
AN
ucle
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eR
TIn
hibi
tor
(NR
TI)
d-d4
FC(D
4FC
)Se
lect
edY
?In
vitr
ose
lect
ion
Gel
eziu
nas0
3
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AA→
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ucle
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hibi
tor
(NR
TI)
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(sta
vudi
ne)
Sele
cted
Y?
Sele
cted
in7
viru
ses
(fro
mpa
tient
isol
ates
or
HX
B2)
thro
ugh
invi
tro
sele
ctio
n.
Gar
cia-
Ler
ma0
3
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AG
AN
ucle
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hibi
tor
(NR
TI)
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(sta
vudi
ne)
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ss-R
Y?
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fold
resi
stan
ceB
azm
i00
92 Drug Resistance Mutations in HIV-1 RT
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Am
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gSe
lect
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nge
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nge
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ssC
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und
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tro
vivo
Com
men
tsR
efs
K65
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ucle
osid
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hibi
tor
(NR
TI)
ddC
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cita
bine
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lect
edY
Y4–
10-f
old
resi
stan
ceZ
hang
94,
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4
K65
RA
AA→
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ucle
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hibi
tor
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TI)
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anos
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Sele
cted
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Infr
eque
ntly
obse
rved
inpa
tient
sre
ceiv
ing
ddI
ordd
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ng94
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AA→
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AN
ucle
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hibi
tor
(NR
TI)
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GSe
lect
edY
?8.
7-fo
ldre
sist
ance
Baz
mi0
0
K65
RA
AA→
AG
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
PME
A(a
defo
vir)
Sele
cted
YN
10–2
5-fo
ldre
sist
ant
Foli9
6
K65
RA
AA→
AG
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
PMPA
(ten
ofov
ir)
Sele
cted
Y?
3.5-
fold
resi
stan
tW
ainb
erg9
9
D67
AG
AC→
GC
CN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)Se
lect
edY
?Se
lect
ion
ofre
sist
ant
HIV
-1E
VK
pass
aged
in
MT-
4ce
lls
Gas
hnik
ova0
3
D67
del
GA
C→
dele
tion
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
+dd
I(d
idan
osin
e)Se
lect
edN
YSe
lect
edby
AZ
T+
ddI.
Litt
leef
fect
alon
e(1
.2-f
old)
,bu
t18
13-f
old
inco
mbi
natio
nw
ithK
103N
,L
74I,
T69
G,
K70
R,
T21
5Yan
dK
219Q
Imam
ichi
00
D67
del
GA
C→
dele
tion
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)dd
C(z
alci
tabi
ne)
Cro
ss-R
NY
Sele
cted
byA
ZT
+dd
Iin
patie
nt.
Site
-dir
ecte
d
mut
ant:
18-f
old.
Imam
ichi
00
D67
del
GA
C→
dele
tion
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)dd
I(d
idan
osin
e)Se
lect
edN
YSe
lect
edby
AZ
T+
ddI
inpa
tient
.Si
te-d
irec
ted
mut
ant:
3.8-
fold
.
Imam
ichi
00
D67
del
GA
C→
del
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)M
DR
(mul
ti-dr
ug
resi
stan
t)
Sele
cted
?Y
3nu
cleo
tide
dele
tion
inm
ulti-
trea
ted
HIV
-1in
fect
edpa
tient
Mas
ciar
i02
D67
EG
AC→
GA
GM
ultip
leN
ucle
osid
eM
DR
(mul
ti-dr
ug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
D67
GG
AC→
GA
GN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
(+)d
OT
FCSe
lect
edY
?R
icha
rd00
D67
GG
AC→
GA
GN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
(+)d
OT
FCC
ross
-RY
?R
icha
rd00
D67
GG
AC→
GG
CM
ultip
leN
ucle
osid
eM
DR
(mul
ti-dr
ug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
D67
NG
AC→
AA
CN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)Se
lect
edY
YD
67N
/K70
R/T
215Y
/K21
9Q:
120-
fold
;M
41L
/D
67N
/K70
R/T
215Y
:18
0-fo
ld.
Lar
der8
9,L
arde
r91,
Kel
lam
92
D67
SG
AC→
?M
ultip
leN
ucle
osid
eM
DR
(mul
ti-dr
ug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
S68
GA
GT→
GG
TM
ultip
leN
ucle
osid
eM
DR
(mul
ti-dr
ug
resi
stan
t)
Sele
cted
?Y
Freq
uent
lyas
soci
ated
with
othe
rm
ulti-
ddN
resi
stan
cem
utat
ions
V75
I,F7
7L,
F116
Yan
dQ
151M
.
Schm
it98
S68
NA
GT→
AA
TM
ultip
leN
ucle
osid
eM
DR
(mul
ti-dr
ug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
S68
NA
GT→
AA
TM
ultip
leN
ucle
osid
eM
DR
(mul
ti-dr
ug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
S68
NR
Tin
hibi
tor
VR
X-3
2974
7Se
lect
edY
Zha
ng06
S68
NR
Tin
hibi
tor
VR
X-4
1363
8Se
lect
edY
Zha
ng06
Drug Resistance Mutations in HIV-1 RT 93
HIV
-1R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
S68
S+
GG
GA
GT→
ins
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
S68
S+
SSA
GT→
ins
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
NY
>25
00-f
old-
Rto
AZ
Tw
hen
inco
m-
bina
tion
with
210W
,21
5Y,
62V
Lar
der9
9
S68
S+
SSG
AG
T→
ins
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
S68
S+
STA
GT→
ins
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
S68
S+
SVA
GT→
ins
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
S68
YA
GT→
TAT
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
ins
69T
RV
MG
AC
T+→
AC
GA
GA
GT
GA
TG
GG
GN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
1592
U89
(aba
cavi
r)C
ross
-RY
Y32
-fol
dre
sist
ance
;du
plic
atio
nof
15
mut
atio
nsof
HIV
-1en
v
Lob
ato0
2
ins
69T
RV
MG
AC
T+→
AC
GA
GA
GT
GA
TG
GG
GN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
3TC
(lam
ivud
ine)
Cro
ss-R
YY
84-f
old
resi
stan
ce;
dupl
icat
ion
of15
mut
atio
nsof
HIV
-1en
v
Lob
ato0
2
ins
69T
RV
MG
AC
T+→
AC
GA
GA
GT
GA
TG
GG
GN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)C
ross
-RY
Y37
1-fo
ldre
sist
ance
;du
plic
atio
nof
15m
utat
ions
ofH
IV-1
env
Lob
ato0
2
ins
69T
RV
MG
AC
T+→
AC
GA
GA
GT
GA
TG
GG
GN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
d4T
(sta
vudi
ne)
Cro
ss-R
YY
15-f
old
resi
stan
ce;
dupl
icat
ion
of15
mut
atio
nsof
HIV
-1en
v
Lob
ato0
2
ins
69T
RV
MG
AC
T+→
AC
GA
GA
GT
GA
TG
GG
GN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
ddC
(zal
cita
bine
)C
ross
-RY
Y4-
fold
resi
stan
ce;
dupl
icat
ion
of15
mut
atio
nsof
HIV
-1en
v
Lob
ato0
2
ins
69T
RV
MG
AC
T+→
AC
GA
GA
GT
GA
TG
GG
GN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
ddI
(did
anos
ine)
Cro
ss-R
YY
12-f
old
resi
stan
ce;
dupl
icat
ion
of15
mut
atio
nsof
HIV
-1en
v
Lob
ato0
2
INS
69T
SGA
CT→
ins
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
+dd
I(d
idan
osin
e)or
ddC
(zal
cita
bine
)
Sele
cted
YY
Hig
hly
resi
stan
tto
3TC
,A
BC
,d4
TB
ulgh
eron
i04
T69
AA
CT→
GC
TM
ultip
leN
ucle
osid
e3T
C(l
amiv
udin
e)+
d4T
(sta
vudi
ne)
Sele
cted
?Y
Seen
inon
epa
tient
on3T
C+
d4T
com
bina
tion
ther
apy.
Law
renc
e99
T69
A+
SGA
CT→
GC
T+
AG
TG
GT
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
?Y
Seen
inhe
avily
trea
ted
patie
nts.
Con
fers
>4-
fold
resi
stan
ceto
:A
ZT,
ddI,
ddC
,3T
Can
dPM
EA
.
Win
ters
98
T69
DA
CT→
GA
TM
ultip
leN
ucle
osid
eA
ZT
(zid
ovud
ine)
+3T
C(l
amiv
udin
e)Se
lect
ed?
YSe
enin
one
patie
nton
AZ
T+
3TC
com
bina
tion
ther
apy.
Law
renc
e99
T69
DA
CT→
GA
TN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
ddC
(zal
cita
bine
)Se
lect
edN
Y5-
fold
resi
stan
ceFi
tzgi
bbon
92
94 Drug Resistance Mutations in HIV-1 RT
HIV
-1R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
T69
GA
CT→
GG
TN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)+
ddI
(did
anos
ine)
Sele
cted
NY
Sele
cted
byA
ZT
+dd
I.L
ittle
effe
ctal
one
(1.5
-fol
d),
but
1813
-fol
din
com
bina
tion
with
K10
3N,
L74
I,T
69G
,K
70R
,T
215Y
and
K21
9Q
Imam
ichi
00
T69
GA
CT→
GG
TN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
ddC
(zal
cita
bine
)C
ross
-RN
YSe
lect
edby
AZ
T+
ddI
inpa
tient
.Si
te-d
irec
ted
mut
ant:
11-f
old.
Imam
ichi
00
T69
GA
CT→
GG
TN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
ddI
(did
anos
ine)
Sele
cted
NY
Sele
cted
byA
ZT
+dd
Iin
patie
nt.
Site
-dir
ecte
d
mut
ant:
10-f
old.
Imam
ichi
00
T69
NA
CT→
AA
TM
ultip
leN
ucle
osid
e3T
C(l
amiv
udin
e)+
d4T
(sta
vudi
ne)
Sele
cted
?Y
Seen
intw
opa
tient
son
3TC
+d4
Tco
mbi
na-
tion
ther
apy.
Law
renc
e99
T69
S+
AG
AC
T→
ins
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
T69
S+
EA
AC
T→
AG
T+
AG
AG
CA
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
?Y
Seen
inhe
avily
trea
ted
patie
nts.
Con
fers
>4-
fold
resi
stan
ceto
:A
ZT,
ddI,
ddC
,3T
Can
dPM
EA
.
Win
ters
98
T69
S+
EE
AC
T→
ins
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
T69
S+
RA
AC
T→
AG
T+
AG
AG
CA
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
?Y
Seen
inhe
avily
trea
ted
patie
nts.
Con
fers
>4-
fold
resi
stan
ceto
:A
ZT,
ddI,
ddC
,3T
Can
dPM
EA
.
Win
ters
98
T69
S+
SAA
CT→
AG
C+
AG
CG
CT
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
?Y
Seen
inhe
avily
trea
ted
patie
nts.
Con
fers
>4-
fold
resi
stan
ceto
:A
ZT,
ddI,
ddC
,3T
Can
dPM
EA
.
Win
ters
98
T69
S+
SAA
CT→
TC
T+
AG
TG
CT
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
?Y
Seen
inhe
avily
trea
ted
patie
nts.
Con
fers
>4-
fold
resi
stan
ceto
:A
ZT,
ddI,
ddC
,3T
Can
dPM
EA
.
Win
ters
98
T69
S+
SAA
CT→
AG
T+
AG
CG
CT
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
?Y
Seen
inhe
avily
trea
ted
patie
nts.
Con
fers
>4-
fold
resi
stan
ceto
:A
ZT,
ddI,
ddC
,3T
Can
dPM
EA
.
Win
ters
98
T69
S+
SGA
CT→
AG
T+
AG
TG
GT
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)dd
I(d
idan
osin
e)+
hydr
oxyu
rea
Sele
cted
?Y
Seen
inon
epa
tient
.D
eAnt
oni9
7
T69
S+
SGA
CT→
AG
T+
AG
TG
GT
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
?Y
Seen
inhe
avily
trea
ted
patie
nts.
Con
fers
>4-
fold
resi
stan
ceto
:A
ZT,
ddI,
ddC
,3T
Can
dPM
EA
.
Win
ters
98
T69
S+
SSA
CT→
AG
T+
AG
TA
GT
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)dd
I(d
idan
osin
e)+
hydr
oxyu
rea
Sele
cted
?Y
Seen
inon
epa
tient
.D
eAnt
oni9
7
Drug Resistance Mutations in HIV-1 RT 95
HIV
-1R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
T69
S+
SSA
CT→
TC
T+
AG
CT
CT
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
?Y
Seen
inhe
avily
trea
ted
patie
nts.
Con
fers
>4-
fold
resi
stan
ceto
:A
ZT,
ddI,
ddC
,3T
Can
dPM
EA
.
Win
ters
98
T69
S+
SSA
CT→
TC
T+
AG
TT
CT
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
?Y
Seen
inhe
avily
trea
ted
patie
nts.
Con
fers
>4-
fold
resi
stan
ceto
:A
ZT,
ddI,
ddC
,3T
Can
dPM
EA
.
Win
ters
98
T69
S+
TG
AC
T→
TC
T+
AC
CG
GT
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti
drug
resi
stan
t)
Sele
cted
?Y
Bul
gher
oni0
4
T69
S+
TS
AC
T→
TC
T+
AC
CT
CT
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
?Y
Seen
inhe
avily
trea
ted
patie
nts.
Con
fers
>4-
fold
resi
stan
ceto
:A
ZT,
ddI,
ddC
,3T
Can
dPM
EA
.
Win
ters
98
T69
S+
VG
AC
T→
ins
Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
Sele
cted
NY
Lar
der9
9
K70
EA
AA→
GA
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
3TC
(lam
ivud
ine)
Cro
ss-R
Y?
PME
A-s
elec
ted
viru
sco
nfer
s7-
fold
resi
stan
ce.
Che
rrin
gton
96
K70
EA
AA→
GA
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
PME
A(a
defo
vir)
Sele
cted
YY
9-fo
ldin
vitr
o.A
lso
seen
inpa
-
tient
son
PME
Ath
erap
y.
Che
rrin
gton
96,
Mill
er98
K70
RA
AA→
AG
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)Se
lect
edY
YD
67N
/K70
R/T
215Y
/K21
9Q:
120-
fold
Lar
der8
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arde
r91,
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lam
92
K70
SA
AA→
AG
AM
ultip
leN
ucle
osid
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idan
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e)+
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vudi
ne)
Sele
cted
?Y
Seen
inon
epa
tient
ondd
C+
d4T
com
bina
tion
ther
apy.
Law
renc
e99
L74
IT
TA→
ATA
HIV
-1Sp
ecifi
cR
TIn
hibi
tor
(NN
RT
I)H
BY
097
Sele
cted
Y?
Kle
im96
L74
VT
TA→
GTA
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)15
92U
89(a
baca
vir)
Sele
cted
YN
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R/L
74V
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ld;
K65
R/L
74V
/M
184V
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old
Tis
dale
97
L74
VT
TA→
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TI
cycl
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GC
ross
-RY
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fold
resi
stan
ceR
ay05
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TA→
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leos
ide
RT
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bito
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RT
I)dd
C(z
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ne)
Cro
ss-R
NY
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-fol
dre
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ant
todd
I-se
lect
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rus
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91
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leos
ide
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bito
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idan
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lect
edN
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anre
vers
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fect
ofT
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sist
ance
mut
atio
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ir91
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TA→
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leos
ide
RT
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bito
r(N
RT
I)D
XG
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cted
Y?
4-fo
ldre
sist
ance
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mi0
0
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VT
TA→
GTA
HIV
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ecifi
cR
TIn
hibi
tor
(NN
RT
I)H
BY
097
Sele
cted
Y?
Kle
im96
V75
IG
TA→
ATA
Nuc
leos
ide
RT
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bito
r(N
RT
I)(-
)dO
TC
Sele
cted
Y?
1.6-
fold
afte
r12
pass
ages
,bu
tse
en
in5
diff
eren
tcl
ones
Ric
hard
99
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IG
TA→
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HIV
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ecifi
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hibi
tor
(NN
RT
I)H
BY
097
Sele
cted
Y?
Com
pens
ates
for
nega
tive
effe
ctof
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0Em
utat
ion
onR
Tac
tivity
Kle
im96
96 Drug Resistance Mutations in HIV-1 RT
HIV
-1R
T
Am
ino
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dC
odon
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gSe
lect
edIn
In
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nge
Cha
nge
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ssC
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und
orC
ross
-Rvi
tro
vivo
Com
men
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efs
V75
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TA→
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Mul
tiple
Nuc
leos
ide
MD
R(m
ulti-
drug
resi
stan
t)
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cted
NY
V75
Ial
one
has
noef
fect
,bu
tin
com
bina
tion
with
mut
atio
nsat
62,
77,
116,
151
caus
esm
ulti
NR
TI
resi
stan
ce.
Shir
asak
a95
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TA→
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HIV
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cR
TIn
hibi
tor
(NN
RT
I)H
BY
097
Sele
cted
Y?
Kle
im96
V75
MG
TA→
AT
GN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
d4T
(sta
vudi
ne)
Sele
cted
NY
Ass
ocia
ted
with
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deE
viru
sA
riyo
shi0
3
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MG
TA→
AT
GM
ultip
leN
ucle
osid
edd
C(z
alci
tabi
ne)
+d4
T(s
tavu
dine
)Se
lect
ed?
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enin
one
patie
nton
ddC
+d4
Tco
mbi
natio
n
ther
apy.
Law
renc
e99
V75
TG
TA→
AC
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
d4C
Cro
ss-R
YN
d4T-
sele
cted
Lac
ey94
V75
TG
TA→
AC
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
d4T
(sta
vudi
ne)
Sele
cted
YN
Obs
erve
dw
ithd4
Tse
lect
ion
invi
tro,
rare
lyin
patie
nts
rece
ivin
gd4
T
Lac
ey94
,L
in99
V75
TG
TA→
AC
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
ddC
(zal
cita
bine
)C
ross
-RY
Nd4
T-se
lect
edL
acey
94
V75
TG
TA→
AC
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
ddI
(did
anos
ine)
Cro
ss-R
YN
d4T-
sele
cted
Lac
ey94
V75
TG
TA→
AC
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
(-)-
FTC
(em
tric
itabi
ne)
Cro
ss-R
YN
d4T-
sele
cted
Lac
ey94
F77
LT
TC→
CT
CM
ultip
leN
ucle
osid
eM
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ti-dr
ug
resi
stan
t)
Sele
cted
NY
F77L
alon
eha
sno
effe
ct,
but
inco
mbi
na-
tion
with
mut
atio
nsat
62,
75,
116,
151
caus
esm
ulti
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TI
resi
stan
ce.
Shir
asak
a95
R83
KN
ucle
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TIn
hibi
tor
(NR
TI)
Sele
cted
YIn
crea
sed
NR
TI
susc
eptib
ility
Svic
her0
6
W88
GT
GG→
GG
GPy
roph
osph
ate
Ana
logu
eR
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hibi
tor
PFA
(fos
carn
et)
Sele
cted
NY
Obs
erve
daf
ter
sele
ctio
nw
ithA
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and
PFA
;su
ppre
sses
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cts
ofA
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mut
atio
nsM
ello
rs95
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ST
GG→
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GPy
roph
osph
ate
Ana
logu
eR
TIn
hibi
tor
PFA
(fos
carn
et)
Sele
cted
NY
Part
ially
supp
ress
esef
fect
sof
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Tre
sist
ance
mut
atio
ns
Mel
lors
95
E89
GG
AA→
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APy
roph
osph
ate
Ana
logu
eR
TIn
hibi
tor
PFA
(fos
carn
et)
Cro
ss-R
YN
Isol
ated
bysc
reen
ing
RT
clon
esfo
rdd
GT
P
resi
stan
ce
Pras
ad91
E89
KG
AA→
GG
APy
roph
osph
ate
Ana
logu
eR
TIn
hibi
tor
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(fos
carn
et)
Sele
cted
YN
Supp
ress
esef
fect
sof
AZ
Tre
sist
ance
mut
atio
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ched
jian9
5
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IT
TA→
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Pyro
phos
phat
eA
nalo
gue
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Inhi
bito
rPF
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osca
rnet
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lect
edY
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rtia
llysu
ppre
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cts
ofA
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stan
ce
mut
atio
ns
Tach
edjia
n95
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CA→
GG
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
L-6
97,6
61Se
lect
edN
YB
yrne
s93
L10
0I
TTA→
ATA
HIV
-1Sp
ecifi
cR
TIn
hibi
tor
(NN
RT
I)B
HA
PU
-882
04E
Sele
cted
Y?
Bal
zari
ni93
d,V
asud
evac
hari
92
L10
0I
TTA→
ATA
HIV
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ecifi
cR
TIn
hibi
tor
(NN
RT
I)B
I-R
G-5
87(n
evir
apin
e)Se
lect
edN
YR
ichm
an93
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0I
TTA→
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HIV
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cR
TIn
hibi
tor
(NN
RT
I)D
MP-
266
(efa
vire
nz)
Sele
cted
YY
Com
bina
tions
ofm
utat
ions
need
edfo
rhi
gh-
leve
lre
sist
ance
;L
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/V10
8I:
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0-fo
ld;
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0I/V
179D
/Y18
1C:
1,00
0-fo
ld
You
ng95
,W
insl
ow96
,
Bac
hele
r00
L10
0I
TTA→
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HIV
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cR
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hibi
tor
(NN
RT
I)L
-697
,661
Sele
cted
YN
Not
inpa
tient
sB
yrne
s93
L10
0I
TTA→
ATA
HIV
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cR
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hibi
tor
(NN
RT
I)T
IBO
R82
150
Sele
cted
Y?
Supp
ress
esef
fect
sof
AZ
Tre
sist
ance
mut
atio
nsM
ello
rs93
,B
alza
rini
93c
L10
0I
TTA→
ATA
HIV
-1Sp
ecifi
cR
TIn
hibi
tor
(NN
RT
I)T
IBO
R82
913
Sele
cted
Y?
Foun
din
com
bina
tion
with
E13
8KL
arde
r92
Drug Resistance Mutations in HIV-1 RT 97
HIV
-1R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
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tro
vivo
Com
men
tsR
efs
L10
0I
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ATA
HIV
-1Sp
ecifi
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hibi
tor
(NN
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I)U
C-6
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lect
edY
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-fol
dre
sist
ance
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zari
ni95
L10
0I
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ATA
HIV
-1Sp
ecifi
cR
TIn
hibi
tor
(NN
RT
I)U
C-7
0Se
lect
edY
?Pa
ssag
e6:
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fold
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khei
t95a
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TTA→
ATA
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tor
(NN
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lect
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?A
ctiv
ityof
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usL
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duce
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ld,
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ec-
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y,co
mpa
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ildty
pe
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zari
ni96
a,B
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rini
96b
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0I
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cR
TIn
hibi
tor
(NN
RT
I)U
C-8
4Se
lect
edY
?Pa
ssag
e6:
>33
3-fo
ldB
uckh
eit9
5a
K10
1E
AA
A→
GA
AH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
AD
AM
IIC
ross
-RY
?>
30-f
old
resi
stan
tag
ains
ta
viru
sis
olat
e,bu
t
not
resi
stan
tag
ains
ta
site
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ecte
dm
utan
t.
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hman
98
K10
1E
AA
A→
GA
AM
ultip
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ucle
osid
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(zid
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ine)
+B
HA
PU
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01E
(ate
vird
ine)
Sele
cted
?Y
Seen
inon
epa
tient
onat
evir
dine
+A
ZT
com
-bi
natio
nth
erap
y.Fo
und
inas
soci
atio
nw
ith
K10
3N.
Dem
eter
98
K10
1E
AA
A→
GA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BI-
RG
-587
(nev
irap
ine)
Cro
ss-R
Y?
15-f
old
toU
C-7
81-s
elec
ted
viru
sB
uckh
eit9
7
K10
1E
AA
A→
GA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
DM
P-26
6(e
favi
renz
)C
ross
-RY
Y17
-fol
din
crea
sein
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You
ng95
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ache
ler0
0
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1E
AA
A→
GA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
L-6
97,6
61Se
lect
edN
YB
yrne
s93
K10
1E
AA
A→
GA
Ano
ncom
petit
ive
RT
inhi
bito
rM
SK-0
76Se
lect
edY
?H
IV-1
Auw
erx0
4
K10
1E
AA
A→
GA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-10
Sele
cted
Y?
Foun
din
com
bina
tion,
K10
1E/Y
181C
:20
0-fo
ldB
uckh
eit9
5a
K10
1E
AA
A→
GA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-38
Sele
cted
YN
Sele
cted
Inco
mbi
natio
nw
ithG
190E
:>
100-
fold
Bal
zari
ni95
K10
1E
AA
A→
GA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-57
Sele
cted
Y?
Sele
cted
inco
mbi
natio
n,K
101E
/Y18
1C:
58-
fold
Buc
khei
t95a
K10
1E
AA
A→
GA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-781
Sele
cted
Y?
By
pass
age
15:
Y18
1C/V
108I
/K10
1E:
>50
0-
fold
Buc
khei
t97
K10
1E
AA
A→
GA
AH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
O40
Cro
ss-R
Y?
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old
toU
C-7
81-s
elec
ted
viru
sB
uckh
eit9
7
K10
1I
AA
A→
ATA
HIV
-1Sp
ecifi
cR
TIn
hibi
tor
(NN
RT
I)U
C-1
6Se
lect
edY
NSe
lect
edin
com
bina
tion
with
G14
1E:
10-f
old
Bal
zari
ni95
K10
1P
AA
A→
CC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
TM
C12
5C
ross
-RY
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linic
alis
olat
ew
ithth
ism
utat
ion
isas
soci
ated
with
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ease
dph
enot
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susc
eptib
ility
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gerh
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1Q
AA
A→
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AH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
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P-26
6(e
favi
renz
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lect
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ache
ler0
0
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1Q
AA
A→
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AH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
LY-3
0004
6H
Cl
(tro
vird
ine)
Sele
cted
Y?
Foun
din
com
bina
tion
with
V10
8IZ
hang
95,
Vra
ng93
98 Drug Resistance Mutations in HIV-1 RT
HIV
-1R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
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tro
vivo
Com
men
tsR
efs
K10
3E
AA
A→
GA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-8
7201
E(a
tevi
rdin
e)Se
lect
ed?
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und
inas
soci
atio
nw
ithY
181C
inon
epa
-tie
nton
mon
othe
rapy
.K
103E
,K
103N
and
Y18
1Cob
serv
edw
ithm
onot
hera
py.
Dem
eter
98
K10
3H
AA
A→
CA
CN
NR
TI
NN
RT
ISe
lect
ed?
Y
K10
3N
AA
A→
AA
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
AD
AM
IIC
ross
-RY
?>
28-f
old.
Test
edag
ains
ta
site
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ecte
dm
utan
t.C
ushm
an98
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3N
AA
A→
AA
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-8
7201
E(a
tevi
rdin
e)Se
lect
ed?
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und
inas
soci
atio
nw
ithY
181C
inse
vera
lpa
tient
son
mon
othe
rapy
.A
lso
seen
inpa
tient
s
onA
TV
+A
ZT
com
bina
tion
ther
apy.
Dem
eter
98
K10
3N
AA
A→
AA
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BI-
RG
-587
(nev
irap
ine)
Sele
cted
NY
Ric
hman
94
K10
3N
AA
A→
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CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
DM
P-26
6(e
favi
renz
)Se
lect
edY
YY
oung
95,
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hele
r00
K10
3N
AA
A→
AA
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
I-E
BU
(em
ivir
ine)
?Y
?Pr
edom
inan
tm
utat
ion
invi
voSe
ki95
K10
3N
AA
A→
AA
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
L-6
97,5
93Se
lect
edY
?K
103N
/Y18
1C:
>1,
000-
fold
Nun
berg
91
K10
3N
AA
A→
AA
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
L-6
97,6
61Se
lect
edY
YK
103N
and
Y18
1Cm
ost
com
mon
with
mon
othe
rapy
Byr
nes9
3,Sa
ag93
K10
3N
AA
A→
AA
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
TIB
OR
8291
3Se
lect
edY
?>
100-
fold
alon
e.K
103N
/Y18
1C:
>1,
000-
fold
Bal
zari
ni93
d
K10
3N
AA
A→
AA
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-10
Sele
cted
YN
5-fo
ldre
sist
ance
Bal
zari
ni95
K10
3N
AA
A→
AA
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-81
Sele
cted
Y?
Bal
zari
ni95
K10
3Q
AA
A→
CA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
L-6
97,6
61Se
lect
edN
YSa
ag93
K10
3R
AA
A→
AG
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
I-E
BU
(em
ivir
ine)
?Y
YB
orro
toE
soda
97
K10
3R
AA
A→
AG
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
LY-3
0004
6H
Cl
(tro
vird
ine)
Sele
cted
Y?
K10
3R/V
179D
:50
0-fo
ld;
Foun
din
com
bina
-tio
nw
ithV
179D
orY
181C
Zha
ng95
,V
rang
93
K10
3R
AA
A→
AG
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
O-(
2-Ph
enox
yet
hyl)
benz
oyl
(phe
nyl)
thio
carb
amat
e17
c
Cro
ss-R
Y?
Low
pote
ncy
also
agai
nst
K10
3N/Y
181C
Ran
ise0
3
K10
3S
AA
A→
AG
TN
NR
TI
NN
RT
ISe
lect
ed?
Ycl
inic
alis
olat
esas
wel
las
site
-dir
ecte
dm
utan
tste
sted
invi
tro
Har
riga
n05
K10
3T
AA
A→
AC
AN
NR
TI
NN
RT
ISe
lect
ed?
Y
K10
3T
AA
A→
AC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
S-11
53Se
lect
edY
?Fu
jiwar
a98
K10
3T
AA
A→
AC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-42
Sele
cted
YN
100-
fold
resi
stan
ceB
alza
rini
95
V10
6A
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
AD
AM
IIC
ross
-RY
?7.
13-f
old.
Test
edag
ains
ta
site
-dir
ecte
d
mut
ant.
Cus
hman
98
V10
6A
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-8
8204
ESe
lect
edY
?V
asud
evac
hari
92
V10
6A
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BI-
RG
-587
(nev
irap
ine)
Sele
cted
YY
Lar
der9
2,R
ichm
an94
Drug Resistance Mutations in HIV-1 RT 99
HIV
-1R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
V10
6A
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
E-E
BU
-dM
Sele
cted
Y?
Bal
zari
ni93
V10
6A
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
S-11
53Se
lect
edY
?V
106A
+F2
27L
:38
7-fo
ldFu
jiwar
a98
V10
6A
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
S-27
20(q
uino
xalin
e)Se
lect
edY
?P2
25H
follo
ws
V10
6A.
Als
ose
enw
ithL
101I
and
Y18
1C.
Dou
ble
and
trip
lem
utan
tshi
ghly
resi
stan
tto
othe
rN
NR
TI’
s,in
clud
ing
MK
C44
2
Pele
man
s97
V10
6A
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
TIB
OR
8291
3Se
lect
edY
?L
arde
r92
V10
6A
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-69
Sele
cted
Y?
Sele
cted
inco
mbi
natio
n,V
106A
/V18
1C:
166-
fold
Buc
khei
t95a
V10
6A
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-82
Sele
cted
Y?
Act
ivity
ofU
C-8
2ve
rsus
L10
0I,
K10
3N,
V10
6A,
E13
8K,
Y18
1Can
dY
188L
redu
ced
by2-
,6-
,1.
5-,
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d20
0-fo
ld,
resp
ec-
tivel
y,co
mpa
red
tow
ildty
pe
Bal
zari
ni96
b,B
alza
rini
96a
V10
6I
GTA→
ATA
HIV
-1Sp
ecifi
cR
TIn
hibi
tor
(NN
RT
I)H
BY
097
Sele
cted
Y?
App
ears
unde
rlo
wer
eddr
ugco
ncen
trat
ion
sele
ctio
n
Kle
im97
V10
6I
NN
RT
IV
RX
-480
773
Sele
cted
YZ
hang
06b
V10
6M
GT
G→
AT
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-9
0152
(del
avir
dine
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ross
-RY
Bre
nner
03
V10
6M
GT
G→
AT
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BI-
RG
-587
(nev
irap
ine)
Cro
ss-R
YB
renn
er03
V10
6M
GT
G→
AT
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
DM
P-26
6(e
favi
renz
)Se
lect
edY
Yse
lect
edin
vitr
oun
der
efav
iren
zpr
essu
rein
Cla
deC
viru
s.A
lso
deve
lope
din
3/6
efav
iren
z-tr
eate
dpa
tient
sw
ithC
lade
C
infe
ctio
n.
Bre
nner
03
V10
8I
GTA→
ATA
HIV
-1Sp
ecifi
cR
TIn
hibi
tor
(NN
RT
I)A
DA
MII
Cro
ss-R
Y?
6.74
-fol
d.Te
sted
agai
nst
asi
te-d
irec
ted
mut
ant.
Cus
hman
98
V10
8I
GTA→
ATA
HIV
-1Sp
ecifi
cR
TIn
hibi
tor
(NN
RT
I)B
I-R
G-5
87(n
evir
apin
e)Se
lect
edN
YR
ichm
an94
V10
8I
GTA→
ATA
HIV
-1Sp
ecifi
cR
TIn
hibi
tor
(NN
RT
I)D
MP-
266
(efa
vire
nz)
Y?
L10
0I/V
108I
:1,
000-
fold
.O
bser
ved
freq
uent
ly
inpa
tient
s.
Win
slow
96,
Bac
hele
r00
V10
8I
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
I-E
BU
(em
ivir
ine)
?Sel
ecte
dY
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ki95
V10
8I
GTA→
GC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
L-6
97,6
61Se
lect
edY
YB
yrne
s93
V10
8I
GTA→
ATA
HIV
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ecifi
cR
TIn
hibi
tor
(NN
RT
I)LY
-300
046
HC
l(t
rovi
rdin
e)Se
lect
edY
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und
inco
mbi
natio
nw
ithK
101Q
Zha
ng95
,V
rang
93
V10
8I
GT
T→
GA
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
TIB
OR
8291
3Se
lect
edN
Y>
100-
fold
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dam
me9
4a
V10
8I
GTA→
ATA
HIV
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ecifi
cR
TIn
hibi
tor
(NN
RT
I)U
C-7
81Se
lect
edY
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ypa
ssag
e10
:55
-fol
d-R
,in
com
bina
tion
with
Y18
1C
Buc
khei
t97
100 Drug Resistance Mutations in HIV-1 RT
HIV
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T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
G11
2S
RT
inhi
bito
rV
RX
-329
747
Sele
cted
YZ
hang
06
G11
2S
RT
inhi
bito
rV
RX
-413
638
Sele
cted
YZ
hang
06
Y11
5F
TAT→
TT
TN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
1592
U89
(aba
cavi
r)Se
lect
edY
NK
65R
/L74
Van
d/or
Y11
5Fw
ithM
184V
:10
fold
;L
74V
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184V
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-fol
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ide
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ulti-
drug
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stan
t)
Sele
cted
NY
F116
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one
has
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fect
,bu
tin
com
bina
tion
with
mut
atio
nsat
62,
75,
77,
151
caus
esm
ulti
NR
TI
resi
stan
ce.
Shir
asak
a95
V11
8I
GT
T→
AT
TN
ucle
osid
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TIn
hibi
tor
(NR
TI)
3TC
(lam
ivud
ine)
Cro
ss-R
NY
Con
fers
mod
erat
ele
vels
ofre
sist
ance
to3T
C(7
–32-
fold
)w
hen
pres
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inan
AZ
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sist
ant
gene
ticba
ckgr
ound
(41L
/67N
/210
W/2
15Y
)
Her
togs
00
V11
8I
RT
inhi
bito
rV
RX
-329
747
Sele
cted
YZ
hang
06
V11
8I
RT
inhi
bito
rV
RX
-413
638
Sele
cted
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hang
06
P11
9S
CC
C→
TC
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RT
I4’
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TSe
lect
edY
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lect
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ong
with
T16
5Aan
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184V
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5
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9S
CC
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TC
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ucle
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tor
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F-dd
A(l
oden
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e)Se
lect
edY
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und
with
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9Dan
d/or
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4F,
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nsat
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ide
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Inhi
bito
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RT
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lect
edY
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her0
6
D12
3G
NN
RT
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RX
-480
774
Sele
cted
YZ
hang
06b
I13
5L
ATA→
AA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-9
0152
(del
avir
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)C
ross
-RN
YId
entifi
edby
logi
stic
regr
essi
onan
alys
is,
con-
firm
edby
mut
agen
esis
stud
ies.
I135
L/L
283I
:
5.0-
fold
resi
stan
ce.
Bro
wn0
0
I13
5L
ATA→
AA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BI-
RG
-587
(nev
irap
ine)
Cro
ss-R
NY
Iden
tified
bylo
gist
icre
gres
sion
anal
ysis
,co
n-fir
med
bym
utag
enes
isst
udie
s.I1
35L
/L28
3I:
4.2-
fold
resi
stan
ce.
Bro
wn0
0
I13
5L
ATA→
AA
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
DM
P-26
6(e
favi
renz
)C
ross
-RN
YId
entifi
edby
logi
stic
regr
essi
onan
alys
is,
con-
firm
edby
mut
agen
esis
stud
ies.
I135
L/L
283I
:
4.1-
fold
resi
stan
ce.
Bro
wn0
0
I13
5M
ATA→
AT
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-9
0152
(del
avir
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ross
-RN
YId
entifi
edby
logi
stic
regr
essi
onan
alys
is,
con-
firm
edby
mut
agen
esis
stud
ies.
I135
M/L
283I
:
4.0-
fold
resi
stan
ce.
Bro
wn0
0
I13
5M
ATA→
AT
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BI-
RG
-587
(nev
irap
ine)
Cro
ss-R
NY
Iden
tified
bylo
gist
icre
gres
sion
anal
ysis
,co
n-fir
med
bym
utag
enes
isst
udie
s.I1
35M
/L28
3I:
4.5-
fold
resi
stan
ce.
Bro
wn0
0
I13
5M
ATA→
AT
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
DM
P-26
6(e
favi
renz
)C
ross
-RN
YId
entifi
edby
logi
stic
regr
essi
onan
alys
is,
con-
firm
edby
mut
agen
esis
stud
ies.
I135
M/L
283I
:
3.2-
fold
resi
stan
ce.
Bro
wn0
0
Drug Resistance Mutations in HIV-1 RT 101
HIV
-1R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
I13
5T
ATA→
AC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-9
0152
(del
avir
dine
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ross
-RN
YId
entifi
edby
logi
stic
regr
essi
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alys
is,
con-
firm
edby
mut
agen
esis
stud
ies.
I135
T/L
283I
:
2.8-
fold
resi
stan
ce.
Bro
wn0
0
I13
5T
ATA→
AC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BI-
RG
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irap
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ss-R
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Iden
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gres
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ysis
,co
n-fir
med
bym
utag
enes
isst
udie
s.I1
35T
/L28
3I:
3.4-
fold
resi
stan
ce.
Bro
wn0
0
I13
5T
ATA→
AC
AH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
DM
P-26
6(e
favi
renz
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ross
-RN
YId
entifi
edby
logi
stic
regr
essi
onan
alys
is,
con-
firm
edby
mut
agen
esis
stud
ies.
I135
T/L
283I
:
2.5-
fold
resi
stan
ce.
Bro
wn0
0
E13
8A
GA
G→
GC
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
TSA
OSe
lect
edN
YM
utat
ion
redu
cing
susc
eptib
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toT
SAO
in
TSA
Oth
erap
yna
ive
patie
nts.
Van
Lae
them
00
E13
8K
GA
G→
AA
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
I-E
BU
(em
ivir
ine)
Sele
cted
YN
Obt
aine
din
the
conc
omita
ntpr
esen
ceof
low
3TC
conc
entr
atio
ns
Bal
zari
ni96
c
E13
8K
GA
G→
AA
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
TIB
OR
8291
3Se
lect
edY
?Fo
und
inco
mbi
natio
nw
ithL
100I
Bal
zari
ni93
c
E13
8K
GA
G→
AA
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
TSA
OSe
lect
edY
?E
138A
(GA
Gto
GC
G)
inT
SAO
-nai
vepa
tient
s
conf
ers
TSA
Ovi
ral
resi
stan
ce
Bal
zari
ni93
a,B
alza
rini
93b
E13
8K
GA
G→
AA
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-82
Sele
cted
Y?
Act
ivity
ofU
C-8
2ve
rsus
L10
0I,
K10
3N,
V10
6A,
E13
8K,
Y18
1Can
dY
188L
redu
ced
by2-
,6-
,1.
5-,
2-,
4-an
d20
0-fo
ld,
resp
ec-
tivel
y,co
mpa
red
tow
ildty
pe
Bal
zari
ni96
b,B
alza
rini
96a
E13
8K
GA
G→
AA
GH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-84
Sele
cted
Y?
Bal
zari
ni95
T13
9I
AC
A→
ATA
HIV
-1Sp
ecifi
cR
TIn
hibi
tor
(NN
RT
I)A
DA
MII
Cro
ss-R
Y?
38-f
old
resi
stan
tag
ains
ta
viru
sis
olat
e,bu
tno
t
test
edag
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her
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ific
RT
Inhi
bito
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NR
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UC
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95
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Inhi
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lect
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mul
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ss-R
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ns
Mel
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95
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edY
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lect
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184V
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5
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GT
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GA
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GT
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TH
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Spec
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RT
Inhi
bito
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NR
TI)
AD
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98
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GT
T→
GA
TH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
DM
P-26
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favi
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lect
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ldW
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GT
T→
GA
TH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
L-6
97,6
61Se
lect
edN
YB
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GT
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RT
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RT
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OR
8291
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lect
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ific
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bito
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NR
TI)
UC
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cted
Y?
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zari
ni96
a
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GT
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GA
GH
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ific
RT
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bito
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TI)
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97,6
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lect
edN
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GT
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TT
TH
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RT
Inhi
bito
r(N
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C12
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Spec
ific
RT
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bito
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TI)
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cted
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ific
RT
Inhi
bito
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TI)
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?>
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old.
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site
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Spec
ific
RT
Inhi
bito
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NR
TI)
α-A
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RT
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Drug Resistance Mutations in HIV-1 RT 103
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lect
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AP
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8204
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Spec
ific
RT
Inhi
bito
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NR
TI)
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RG
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cted
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lect
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lect
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fold
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com
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TH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
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cted
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fold
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ific
RT
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bito
r(N
NR
TI)
E-E
BU
Sele
cted
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Bal
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Spec
ific
RT
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bito
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TI)
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cted
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4
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RT
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lect
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RT
Inhi
bito
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NR
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lect
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ific
RT
Inhi
bito
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RT
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lect
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RT
Inhi
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yet
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3
Y18
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Spec
ific
RT
Inhi
bito
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OR
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lect
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ific
RT
Inhi
bito
r(N
NR
TI)
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cted
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din
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Spec
ific
RT
Inhi
bito
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NR
TI)
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cted
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Pass
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Y18
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TH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-38
Sele
cted
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pass
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fold
Buc
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Y18
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TAT→
TG
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-57
Sele
cted
Y?
Sele
cted
inco
mbi
natio
n,K
101E
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1C:
58-
fold
Buc
khei
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Y18
1C
TAT→
TG
TH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
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Sele
cted
Y?
Pass
age
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TH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
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Sele
cted
Y?
Pass
age
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fold
Buc
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Y18
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TH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
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Sele
cted
Y?
Sele
cted
inco
mbi
natio
n,V
106A
/V18
1C:
166-
fold
Buc
khei
t95a
Y18
1C
TAT→
TG
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
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Sele
cted
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pass
age
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TH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-80
(NSC
6394
75)
Sele
cted
Y?
Pass
age
6:18
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dB
uckh
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5a
Y18
1C
TAT→
TG
TH
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-81
Cro
ss-R
Y?
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zari
ni95
104 Drug Resistance Mutations in HIV-1 RT
HIV
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T
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ino
Aci
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odon
Dru
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lect
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Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
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cted
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Pass
age
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Buc
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Y18
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RT
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Sele
cted
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TG
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Spec
ific
RT
Inhi
bito
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AT
TH
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ific
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Inhi
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ivir
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ni96
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RT
Inhi
bito
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NR
TI)
TM
C12
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linic
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ew
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ated
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Y18
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Spec
ific
RT
Inhi
bito
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lect
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AT
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leos
ide
RT
Inhi
bito
r(N
RT
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TC
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cted
Y?
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cted
in<
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4I
AT
G→
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leos
ide
RT
Inhi
bito
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RT
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ss-R
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hard
00
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4I
AT
G→
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leos
ide
RT
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bito
r(N
RT
I)(-
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ss-R
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hard
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AT
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leos
ide
RT
Inhi
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r(N
RT
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lect
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AT
G→
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ecifi
cR
TIn
hibi
tor
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RT
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YL
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Cro
ss-R
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gan9
6,
Hoo
ker9
6
R21
1K
AG
G→
AA
GM
ultip
leN
ucle
osid
eA
ZT
(zid
ovud
ine)
+3T
C(l
amiv
udin
e)C
ross
-R?
YPo
lym
orph
ism
faci
litat
ing
AZ
T+
3TC
dual
re-
sist
ance
inas
soci
atio
nw
ithM
184V
and
othe
rA
ZT
resi
stan
cem
utat
ions
.
Kem
p98
L21
4F
CT
T→
TT
TN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)Se
lect
edY
?Se
lect
ion
ofre
sist
ant
HIV
-1E
VK
pass
aged
in
MT-
4ce
lls
Gas
hnik
ova0
3
L21
4F
CT
T→
TT
TN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
ph-A
ZT
Sele
cted
Y?
Sele
ctio
nof
resi
stan
tH
IV-1
EV
Kpa
ssag
edin
MT-
4ce
lls
Gas
hnik
ova0
3
T21
5F
AC
C→
TT
CN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)Se
lect
ed?
YK
67N
/K70
R/T
215Y
/K21
9Q:
120-
fold
Lar
der8
9,L
arde
r91,
Kel
lam
92
108 Drug Resistance Mutations in HIV-1 RT
HIV
-1R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
T21
5Y
AC
C→
TAC
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
Sele
cted
YY
M41
L/T
215Y
:60
–70-
fold
;K
67N
/K70
R/
T21
5Y/K
219Q
:12
0-fo
ld.
Eff
ect
ofT
215Y
isre
vers
edby
add
Im
utat
ion
(L74
V),
NN
RT
Im
utat
ions
(L10
0I;Y
181C
)or
(-)-
FTC
/3T
Cm
u-ta
tions
(M18
4I/V
)
Lar
der8
9,L
arde
r91,
Kel
lam
92
D21
8E
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)Se
lect
edY
Svic
her0
6
K21
9E
AA
A→
GA
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)Se
lect
edY
NL
arde
r89,
Lar
der9
1,K
ella
m92
K21
9E
AA
A→
GA
AN
RT
IPM
PA(t
enof
ovir
)Se
lect
ed?
YW
irde
n05
K21
9N
AA
A→
AA
TN
RT
IPM
PA(t
enof
ovir
)Se
lect
ed?
YW
irde
n05
K21
9Q
AA
A→
CA
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)Se
lect
ed?
YK
67N
/K70
R/T
215Y
/K21
9Q:
120-
fold
Lar
der8
9,L
arde
r91,
Kel
lam
92
K21
9R
AA
A→
AG
AM
ultip
leN
ucle
osid
e3T
C(l
amiv
udin
e)+
d4T
(sta
vudi
ne)
Sele
cted
?Y
Seen
intw
opa
tient
on3T
C+
d4T
com
bina
-
tion
ther
apy.
Law
renc
e99
K21
9R
AA
A→
AG
AM
ultip
leN
ucle
osid
eA
ZT
(zid
ovud
ine)
+3T
C(l
amiv
udin
e)Se
lect
ed?
YSe
enin
two
patie
nton
AZ
T+
3TC
com
bina
-
tion
ther
apy.
Law
renc
e99
K21
9W
AA
A→
TG
GM
ultip
leN
ucle
osid
edd
C(z
alci
tabi
ne)
+d4
T(s
tavu
dine
)Se
lect
ed?
YSe
enin
one
patie
nton
ddC
+d4
Tco
mbi
natio
n
ther
apy.
Law
renc
e99
P22
5H
CC
T→
CA
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
DM
P-26
6(e
favi
renz
)Se
lect
edN
YO
bser
ved
freq
uent
lyin
patie
nts.
Bac
hele
r00
P22
5H
CC
T→
CA
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
HB
Y09
7C
ross
-RY
?S-
2720
-sel
ecte
ddo
uble
mut
ant
V10
6A/P
225H
:4.
0-fo
ldPe
lem
ans9
7
P22
5H
CC
T→
CA
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
I-E
BU
(em
ivir
ine)
Cro
ss-R
Y?
S-27
20-s
elec
ted
doub
lem
utan
tV
106A
/P22
5H:
5.7-
fold
Pele
man
s97
P22
5H
CC
T→
CA
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
S-27
20(q
uino
xalin
e)Se
lect
edY
?P2
25H
follo
ws
V10
6A.
Als
ose
enw
ithL
101I
and
Y18
1C.
Pele
man
s97
P22
5H
CC
T→
CA
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
UC
-781
Cro
ss-R
Y?
S-27
20-s
elec
ted
doub
lem
utan
tV
106A
/P22
5H:
3.7-
fold
Pele
man
s97
F22
7C
TT
C→
TG
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
TM
C12
5C
ross
-RY
YV
inge
rhoe
ts04
F22
7L
TTA→
CT
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
S-11
53Se
lect
edY
?V
106A
+F2
27L
:38
7-fo
ld.
Thi
sm
utat
ion
con-
fers
hype
rsen
sitiv
ityto
dela
vird
ine.
Fujiw
ara9
8
F22
7L
NN
RT
IV
RX
-480
776
Sele
cted
YZ
hang
06b
V23
3E
GA
A→
GTA
Mul
tiple
Nuc
leos
ide
AZ
T(z
idov
udin
e)+
BH
AP
U-8
7201
E(a
tevi
rdin
e)
Sele
cted
NY
Seen
in1
patie
nt.
K10
1E,
Y18
8Han
dK
238T
also
seen
inpa
tient
son
AT
V/A
ZT
com
bina
tion
ther
apy.
Dem
eter
98
L23
4I
CT
C→
AT
CH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
S-11
53Se
lect
edY
?T
his
mut
atio
nco
nfer
shy
pers
ensi
tivity
to
lovi
ride
.
Fujiw
ara9
8
P23
6L
CC
T→
CT
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-8
7201
E(a
tevi
rdin
e)Se
lect
edY
?Se
nsiti
zes
RT
10-f
old
tone
vira
pine
,T
IBO
R82
913
and
L-6
97,6
61
Due
wek
e93
Drug Resistance Mutations in HIV-1 RT 109
HIV
-1R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
P23
6L
CC
T→
CT
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-9
0152
(del
avir
dine
)Se
lect
edY
?Se
nsiti
zes
RT
10-f
old
tone
vira
pine
,T
IBO
R82
913
and
L-6
97,6
61
Due
wek
e93
P23
6L
CC
T→
CT
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
HE
PTSe
lect
edY
?B
uckh
eit9
5c
K23
8S
AA
A→
AG
TN
NR
TI
BI-
RG
-587
(nev
irap
ine)
Cro
ss-R
YY
Hac
hiya
04
K23
8T
AA
A→
AC
AM
ultip
leN
ucle
osid
eA
ZT
(zid
ovud
ine)
+B
HA
PU
-872
01E
(ate
vird
ine)
Sele
cted
NY
Seen
in1
patie
nt.
K10
1E,
K10
3N,
Y18
8H,
and
V23
3Eal
soob
serv
edw
ithA
TV
/AZ
Tco
m-
bina
tion
ther
apy.
Dem
eter
98
K23
8T
AA
A→
AC
AM
ultip
leN
ucle
osid
eA
ZT
(zid
ovud
ine)
+B
HA
PU
-872
01E
(ate
vird
ine)
Sele
cted
NY
Seen
in1
patie
nt.
K10
1E,
K10
3N,
Y18
8Han
dE
233V
also
seen
inpa
tient
son
AT
V/A
ZT
com
bina
tion
ther
apy.
Dem
eter
98
L28
3I
CT
T→
AC
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-9
0152
(del
avir
dine
)C
ross
-RN
YId
entifi
edby
logi
stic
regr
essi
onan
alys
is,
con-
firm
edby
mut
agen
esis
stud
ies.
Con
fers
resi
s-ta
nce
inco
njun
ctio
nw
ithm
utat
ions
atco
don
135.
Bro
wn0
0
L28
3I
CT
T→
AC
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BI-
RG
-587
(nev
irap
ine)
Cro
ss-R
NY
Iden
tified
bylo
gist
icre
gres
sion
anal
ysis
,co
n-fir
med
bym
utag
enes
isst
udie
s.C
onfe
rsre
sis-
tanc
ein
conj
unct
ion
with
mut
atio
nsat
codo
n
135.
Bro
wn0
0
L28
3I
CT
T→
AC
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
DM
P-26
6(e
favi
renz
)C
ross
-RN
YId
entifi
edby
logi
stic
regr
essi
onan
alys
is,
con-
firm
edby
mut
agen
esis
stud
ies.
Con
fers
resi
s-ta
nce
inco
njun
ctio
nw
ithm
utat
ions
atco
don
135.
Bro
wn0
0
E31
2Q
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
Sele
cted
YN
ikol
enka
06
Y31
8F
TAT→
TT
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BH
AP
U-9
0152
(del
avir
dine
)C
ross
-RY
YT
his
mut
atio
nal
soac
tssy
nerg
istic
ally
with
K10
3Nan
dY
181C
toco
nfer
high
erle
vels
ofre
sist
ance
toD
LVan
dE
FVth
anse
enw
ithei
ther
ofth
ese
mut
atio
nsal
one
Har
riga
n02,
Pele
man
s98
Y31
8F
TAT→
TT
TH
IV-1
Spec
ific
RT
Inhi
bito
r(N
NR
TI)
BI-
RG
-587
(nev
irap
ine)
Cro
ss-R
YY
Thi
sm
utat
ion
also
acts
syne
rgis
tical
lyw
ithK
103N
and
Y18
1Cto
conf
erhi
gher
leve
lsof
resi
stan
ceto
DLV
and
EFV
than
seen
with
eith
erof
thes
em
utat
ions
alon
e
Har
riga
n02,
Pele
man
s98
G33
3D
GG
C→
GA
CM
ultip
leN
ucle
osid
eA
ZT
(zid
ovud
ine)
+3T
C(l
amiv
udin
e)C
ross
-RY
YFa
cilit
ates
dual
resi
stan
ceto
AZ
T+
3TC
inas
-so
ciat
ion
with
M18
4Van
dst
anda
rdA
ZT
resi
s-ta
nce
mut
atio
ns.
Kem
p98
110 Drug Resistance Mutations in HIV-1 RT
HIV
-1R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
G33
3D
GG
C→
GA
CM
ultip
leN
ucle
osid
eA
ZT
(zid
ovud
ine)
+3T
C(l
amiv
udin
e)+
1592
U89
(aba
cavi
r)
Cro
ss-R
?Y
foun
din
non-
Bsu
btyp
esC
arid
e00
G33
3E
GG
C→
GA
GM
ultip
leN
ucle
osid
eA
ZT
(zid
ovud
ine)
+3T
C(l
amiv
udin
e)C
ross
-RY
YFa
cilit
ates
dual
resi
stan
ceto
AZ
T+
3TC
inas
-so
ciat
ion
with
M18
4Van
dst
anda
rdA
ZT
resi
s-ta
nce
mut
atio
ns.
Kem
p98
G33
3E
GG
C→
GA
GM
ultip
leN
ucle
osid
eA
ZT
(zid
ovud
ine)
+3T
C(l
amiv
udin
e)+
1592
U89
(aba
cavi
r)
Cro
ss-R
?Y
foun
din
non-
Bsu
btyp
esC
arid
e00
G33
5C
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
Sele
cted
YN
ikol
enka
06
G33
5D
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
Sele
cted
YN
ikol
enka
06
N34
8I
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
Sele
cted
YN
ikol
enka
06
A36
0I
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
Sele
cted
YN
ikol
enka
06
A36
0V
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
Sele
cted
YN
ikol
enka
06
V36
5I
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
Sele
cted
YN
ikol
enka
06
T36
9I
NN
RT
IV
RX
-480
775
Sele
cted
YZ
hang
06b
A37
6S
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
Sele
cted
YN
ikol
enka
06
T38
6I
AC
T→
AT
TM
ultip
leN
ucle
osid
eA
ZT
(zid
ovud
ine)
+3T
C(l
amiv
udin
e)+
1592
U89
(aba
cavi
r)
Cro
ss-R
?Y
Abr
ogat
esM
184V
supp
ress
ion
ofL
210W
and
L21
0W/G
333D
/E
Car
ide0
0
Drug Resistance Mutations in HIV-2 RT 111
HIV
-2R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
I5
VN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)+
3TC
(lam
ivud
ine)
+dd
I(d
idan
osin
e)
Sele
cted
?Y
Bra
ndin
03
I5
VA
TT→
GT
TN
RT
Im
ulti-
nucl
eosi
deSe
lect
ed?
YC
olso
n05
I10
VN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
1592
U89
(aba
cavi
r)+
3TC
(lam
ivud
ine)
+A
ZT
(zid
ovud
ine)
Sele
cted
?Y
Bra
ndin
03
I10
VN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)+
3TC
(lam
ivud
ine)
+dd
I(d
idan
osin
e)
Sele
cted
?Y
Bra
ndin
03
V11
IN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)+
3TC
(lam
ivud
ine)
+dd
I(d
idan
osin
e)
Sele
cted
?Y
Bra
ndin
03
R20
KN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
1592
U89
(aba
cavi
r)+
3TC
(lam
ivud
ine)
+A
ZT
(zid
ovud
ine)
Sele
cted
?Y
Bra
ndin
03
K35
RA
AA→
AG
AN
RT
Im
ulti-
nucl
eosi
deSe
lect
ed?
YC
olso
n05
R35
KN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
1592
U89
(aba
cavi
r)+
3TC
(lam
ivud
ine)
+A
ZT
(zid
ovud
ine)
Sele
cted
?Y
Bra
ndin
03
K40
RN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
1592
U89
(aba
cavi
r)+
3TC
(lam
ivud
ine)
+A
ZT
(zid
ovud
ine)
Sele
cted
?Y
Bra
ndin
03
I43
IN
ucle
osid
eR
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hibi
tor
(NR
TI)
AB
T-53
8(ri
tona
vir)
+A
G-1
343
(nel
finav
ir)
Sele
cted
?Y
Bra
ndin
03
K45
RN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AB
T-53
8(ri
tona
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+A
G-1
343
(nel
finav
ir)
Sele
cted
?Y
Bra
ndin
03
G48
AN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YB
rand
in03
I50
VN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YB
rand
in03
I54
MN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AB
T-53
8(ri
tona
vir)
+A
G-1
343
(nel
finav
ir)
Sele
cted
?Y
Bra
ndin
03
112 Drug Resistance Mutations in HIV-2 RT
HIV
-2R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
I64
VN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AB
T-37
8(l
opin
avir
)Se
lect
ed?
YB
rand
in03
K65
RN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)+
3TC
(lam
ivud
ine)
+dd
I(d
idan
osin
e)
Sele
cted
?Y
Bra
ndin
03
N69
SN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AZ
T(z
idov
udin
e)+
3TC
(lam
ivud
ine)
+dd
I(d
idan
osin
e)
Sele
cted
?Y
Bra
ndin
03
K70
SN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
1592
U89
(aba
cavi
r)+
3TC
(lam
ivud
ine)
+A
ZT
(zid
ovud
ine)
Sele
cted
?Y
Bra
ndin
03
V71
IN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AB
T-53
8(ri
tona
vir)
+A
G-1
343
(nel
finav
ir)
Sele
cted
?Y
Bra
ndin
03
A92
TN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AB
T-53
8(ri
tona
vir)
+A
G-1
343
(nel
finav
ir)
Sele
cted
?Y
Bra
ndin
03
L99
FN
ucle
osid
eR
TIn
hibi
tor
(NR
TI)
AB
T-53
8(ri
tona
vir)
+A
G-1
343
(nel
finav
ir)
Sele
cted
?Y
Bra
ndin
03
A10
1P
GC
C→
CC
Cno
ncom
petit
ive
RT
inhi
bito
rM
SK-0
76Se
lect
edY
?M
utat
ion
foun
din
HIV
-2at
apo
sitio
neq
uiva
-
lent
toth
eN
NR
TI
bind
ing
site
inH
IV-1
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erx0
4
G11
2E
GG
G→
GA
Gno
ncom
petit
ive
RT
inhi
bito
rM
SK-0
76Se
lect
edY
?M
utat
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foun
dcl
ose
toth
eH
IV-2
activ
esi
teA
uwer
x04
Q15
1M
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
ine)
+3T
C(l
amiv
udin
e)+
ddI
(did
anos
ine)
Sele
cted
?Y
Bra
ndin
03
Y16
2H
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
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+3T
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amiv
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ddI
(did
anos
ine)
Sele
cted
?Y
Bra
ndin
03
T16
3A
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)15
92U
89(a
baca
vir)
+3T
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amiv
udin
e)+
AZ
T(z
idov
udin
e)
Sele
cted
?Y
Bra
ndin
03
M18
4V
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
I)3T
C(l
amiv
udin
e)Se
lect
ed?
YB
rand
in03
Drug Resistance Mutations in HIV-2 RT 113
HIV
-2R
T
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
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tro
vivo
Com
men
tsR
efs
F21
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Nuc
leos
ide
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Inhi
bito
r(N
RT
I)A
ZT
(zid
ovud
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+3T
C(l
amiv
udin
e)+
ddI
(did
anos
ine)
Sele
cted
?Y
Bra
ndin
03
F21
4L
TT
T→
CT
TN
RT
Im
ulti-
nucl
eosi
deSe
lect
ed?
YC
olso
n05
E21
9D
Nuc
leos
ide
RT
Inhi
bito
r(N
RT
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ZT
(zid
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Sele
cted
?Y
Bra
ndin
03
K22
3R
AA
A→
AG
AN
RT
Im
ulti-
nucl
eosi
deSe
lect
ed?
YC
olso
n05
114 Drug Resistance Mutations in SIV RT
SIV
RT
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
K65
RA
AA→
AG
ASI
VN
ucle
osid
eR
TIn
hibi
tor
PMPA
(ten
ofov
ir)
Sele
cted
?Y
K65
Rap
pear
sfir
st,
follo
wed
byN
69S
and
I118
V.
Obs
erve
dch
ange
sat
N69
San
dI1
18V
dono
tre
sult
inin
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sed
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stan
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Rom
pay9
6,C
herr
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on96
a,
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Rom
pay9
7a
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G→
AT
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VN
ucle
osid
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TIn
hibi
tor
AZ
T(z
idov
udin
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lect
ed?
YV
anR
ompa
y97
Drug Resistance Mutations in HIV-1 Integrase 115
HIV
-1In
tegr
ase
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
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vivo
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men
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efs
T66
IIn
tegr
ase
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bito
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ihyd
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phen
e
(DH
T)
Cro
ssR
YD
oubl
em
utan
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66I/
N15
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nfer
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ldre
sist
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whi
letr
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mut
ants
T66
I/S1
53Y
/N
155S
conf
ers
grea
ter
than
33fo
ldre
sist
ance
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HT
sar
ea
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lse
ries
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;tw
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bed
inth
ispa
per
DH
T-1
and
DH
T-2.
Keh
lenb
eck0
6
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GG
C→
AG
CIn
tegr
ase
inhi
bito
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-Chi
cori
cA
cid
Sele
cted
Y?
Mut
atio
nlo
cate
din
the
cata
lytic
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ofin
te-
gras
e.M
ildly
atte
ntua
tes
viru
sgr
owth
.
Kin
g98
S15
3Y
Inte
gras
eIn
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tor
Dih
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nfer
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ldre
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ance
whi
letr
iple
mut
ants
T66
I/S1
53Y
/N
155S
conf
ers
grea
ter
than
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sar
ea
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lse
ries
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;tw
oar
ede
scri
bed
inth
ispa
per
DH
T-1
and
DH
T-2.
Keh
lenb
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6
N15
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Inte
gras
eIn
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tor
Dih
ydro
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ioph
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oubl
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utan
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66I/
N15
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nfer
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5fo
ldre
sist
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whi
letr
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mut
ants
T66
I/S1
53Y
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ers
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ter
than
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ea
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lse
ries
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;tw
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bed
inth
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per
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T-1
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Keh
lenb
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6
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Inte
gras
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tor
FZ41
Sele
cted
?Y
sele
cted
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njun
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;do
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conf
ers
9fo
ldre
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Bon
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4
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inte
gras
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-dik
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ross
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?on
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inte
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Inte
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conf
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ldre
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ance
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nenf
ant0
4
116 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
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und
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ross
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vivo
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men
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efs
Q32
HFu
sion
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ding
Inhi
bito
rT
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enta
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bito
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lect
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ness
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reng
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Res
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8
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ding
Inhi
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ding
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bito
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V38
MG
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ding
Inhi
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cted
Y?
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bito
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lect
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TA
AC→
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nfuv
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lect
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AT→
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bito
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nfuv
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lect
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bito
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lect
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04
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bito
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lect
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lect
edY
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lect
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Yre
pres
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aco
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bito
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Lab
ross
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bito
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ding
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ding
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lpha
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Sele
cted
YN
DV
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oop
Reg
ion
Est
e96a
,E
ste9
7
Drug Resistance Mutations in HIV-1 Env 117
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
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tro
vivo
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men
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lect
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ross
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rSD
F-1α
Sele
cted
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
15-f
old.
Scho
ls98
F14
5L
TT
C→
TTA
Fusi
on/B
indi
ngIn
hibi
tor
JM27
63C
ross
Res
ista
ntY
?10
6K/1
34N
/145
L/2
45I/
269E
/278
H/2
88V
/293
D/
364–
367D
elet
ion/
387T
:10
fold
Scho
ls98
F14
5L
TT
C→
TTA
Fusi
on/B
indi
ngIn
hibi
tor
JM-3
100
Sele
cted
Y?
Com
bina
tion
ofm
utat
ions
:2-
to10
0-fo
ldD
eVre
ese9
6,D
eVre
ese9
6a
F14
5L
TT
C→
TTA
Fusi
on/B
indi
ngIn
hibi
tor
JM-3
100
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
10-f
old
Scho
ls98
F14
5L
TT
C→
TTA
Fusi
on/B
indi
ngIn
hibi
tor
Mab
12G
5C
ross
Res
ista
ntY
?10
6K/1
34N
/145
L/2
45I/
269E
/278
H/2
88V
/293
D/
364–
367D
elet
ion/
387T
:Sc
hols
98
F14
5L
TT
C→
TTA
Fusi
on/B
indi
ngIn
hibi
tor
SDF-
1 αSe
lect
edY
?10
6K/1
34N
/145
L/2
45I/
269E
/278
H/2
88V
/293
D/
364–
367D
elet
ion/
387T
:15
-fol
d.Sc
hols
98
N18
8K
AA
T→
AA
AFu
sion
/Bin
ding
Inhi
bito
rsi
amyc
inI
Sele
cted
Y?
N18
8K/G
332E
/N35
1D/A
550T
/N63
3D/L
762S
:9-
fold
Lin
96
P20
3L
Ent
ryIn
hibi
tor
Am
phot
eric
inB
Met
hyl
Est
er(A
ME
)
Sele
cted
YM
utat
ions
sele
cted
inth
ecy
topl
asm
icta
ilof
gp41
Wah
eed0
6
N20
4K
entr
yin
hibi
tor
Con
cana
valin
A(C
onA
)Se
lect
edY
?m
utat
ions
ingp
120
Witv
rouw
05
S20
5L
Ent
ryIn
hibi
tor
Am
phot
eric
inB
Met
hyl
Est
er(A
ME
)
Sele
cted
YM
utat
ions
sele
cted
inth
ecy
topl
asm
icta
ilof
gp42
Wah
eed0
6
G23
7R
Fusi
on/B
indi
ngIn
hibi
tor
IC95
64(e
miv
irin
e)Se
lect
edY
?gp
-120
Hol
z-Sm
ith01
F24
5I
TT
C→
AT
CFu
sion
/Bin
ding
Inhi
bito
rJM
2763
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
10fo
ldSc
hols
98
F24
5I
TT
C→
AT
CFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0C
ross
Res
ista
ntY
?10
6K/1
34N
/145
L/2
45I/
269E
/278
H/2
88V
/293
D/
364–
367D
elet
ion/
387T
:10
-fol
dSc
hols
98
F24
5I
TT
C→
AT
CFu
sion
/Bin
ding
Inhi
bito
rM
ab12
G5
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
Scho
ls98
118 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
F24
5I
TT
C→
AT
CFu
sion
/Bin
ding
Inhi
bito
rSD
F-1α
Sele
cted
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
15-f
old.
Scho
ls98
R25
2K
Fusi
on/B
indi
ngIn
hibi
tor
IC95
64(e
miv
irin
e)Se
lect
edY
?gp
-120
Hol
z-Sm
ith01
S26
1F
entr
yin
hibi
tor
Con
cana
valin
A(C
onA
)Se
lect
edY
?m
utat
ions
ingp
120
Witv
rouw
05
K26
9E
AA
A→
GA
AFu
sion
/Bin
ding
Inhi
bito
rD
S(d
extr
ansu
lpha
te)
Sele
cted
Y?
V3
loop
regi
on;
S113
N/S
134N
/K26
9E/Q
278E
/
N29
3D/N
323S
/R38
7I:
250-
fold
Est
e97,
Est
e96a
N26
9E
AA
C→
GA
AFu
sion
/Bin
ding
Inhi
bito
rJM
2763
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
10fo
ldSc
hols
98
N26
9E
AA
C→
GA
AFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0C
ross
Res
ista
ntY
?10
6K/1
34N
/145
L/2
45I/
269E
/278
H/2
88V
/293
D/
364–
367D
elet
ion/
387T
:10
-fol
dSc
hols
98
N26
9E
AA
C→
GA
AFu
sion
/Bin
ding
Inhi
bito
rM
ab12
G5
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
Scho
ls98
N26
9E
AA
C→
GA
AFu
sion
/Bin
ding
Inhi
bito
rSD
F-1α
Sele
cted
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
15-f
old.
Scho
ls98
N26
9K
AA
C→
?Fu
sion
/Bin
ding
Inhi
bito
rA
LX
40–4
CC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
145-
fold
cros
s-re
sist
ant
toA
LX
40–4
C.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
Kan
bara
01
N26
9K
AA
C→
?Fu
sion
/Bin
ding
Inhi
bito
rA
MD
3100
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)15
-fol
dcr
oss-
resi
stan
tto
AM
D31
00.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
N26
9K
AA
C→
?Fu
sion
/Bin
ding
Inhi
bito
rSD
F-1
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)26
-fol
dcr
oss-
resi
stan
tto
SDF-
1.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
Drug Resistance Mutations in HIV-1 Env 119
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
N26
9K
AA
C→
?Fu
sion
/Bin
ding
Inhi
bito
rT
134
Sele
cted
YN
Invi
tro
sele
cted
viru
s(p
145
ofH
IV-1
NL
4–3,
cont
ains
mut
atio
nsN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5in
V3
loop
ofgp
120
)15
-fol
dre
sist
ant
to
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
N26
9K
AA
C→
?Fu
sion
/Bin
ding
Inhi
bito
rT
140
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)21
-fol
dcr
oss-
resi
stan
tto
T14
0.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
N26
9K
AA
C→
?Fu
sion
/Bin
ding
Inhi
bito
rvM
IP-I
IC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
42-f
old
cros
s-re
sist
ant
tovM
IPII
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
N27
0S
AA
T→
AG
TFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
R27
2T
AG
A→
AC
AFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
S27
4de
lFu
sion
/Bin
ding
Inhi
bito
rA
LX
40–4
CC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
145-
fold
cros
s-re
sist
ant
toA
LX
40–4
C.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
Kan
bara
01
S27
4de
lFu
sion
/Bin
ding
Inhi
bito
rA
MD
3100
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)15
-fol
dcr
oss-
resi
stan
tto
AM
D31
00.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
120 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
S27
4de
lFu
sion
/Bin
ding
Inhi
bito
rSD
F-1
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)26
-fol
dcr
oss-
resi
stan
tto
SDF-
1.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
S27
4de
lFu
sion
/Bin
ding
Inhi
bito
rT
134
Sele
cted
YN
Invi
tro
sele
cted
viru
s(p
145
ofH
IV-1
NL
4–3,
cont
ains
mut
atio
nsN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5in
V3
loop
ofgp
120
)15
-fol
dre
sist
ant
to
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
S27
4de
lFu
sion
/Bin
ding
Inhi
bito
rT
140
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)21
-fol
dcr
oss-
resi
stan
tto
T14
0.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
S27
4de
lFu
sion
/Bin
ding
Inhi
bito
rvM
IP-I
IC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
42-f
old
cros
s-re
sist
ant
tovM
IPII
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
S27
4R
AG
T→
AG
AFu
sion
/Bin
ding
Inhi
bito
rJM
-276
3Se
lect
edY
?C
ombi
natio
nof
mut
atio
ns:
95-
to79
2-fo
ldD
eVre
ese9
6,D
eVre
ese9
6a
S27
4R
AG
T→
AG
AFu
sion
/Bin
ding
Inhi
bito
rJM
-276
3Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
S27
4R
AG
T→
AG
AFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
I27
5de
lFu
sion
/Bin
ding
Inhi
bito
rA
LX
40–4
CC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
145-
fold
cros
s-re
sist
ant
toA
LX
40–4
C.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
Kan
bara
01
Drug Resistance Mutations in HIV-1 Env 121
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
I27
5de
lFu
sion
/Bin
ding
Inhi
bito
rA
MD
3100
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)15
-fol
dcr
oss-
resi
stan
tto
AM
D31
00.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
I27
5de
lFu
sion
/Bin
ding
Inhi
bito
rSD
F-1
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)26
-fol
dcr
oss-
resi
stan
tto
SDF-
1.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
I27
5de
lFu
sion
/Bin
ding
Inhi
bito
rT
134
Sele
cted
YN
Invi
tro
sele
cted
viru
s(p
145
ofH
IV-1
NL
4–3,
cont
ains
mut
atio
nsN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5in
V3
loop
ofgp
120
)15
-fol
dre
sist
ant
to
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
I27
5de
lFu
sion
/Bin
ding
Inhi
bito
rT
140
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)21
-fol
dcr
oss-
resi
stan
tto
T14
0.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
I27
5de
lFu
sion
/Bin
ding
Inhi
bito
rvM
IP-I
IC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
42-f
old
cros
s-re
sist
ant
tovM
IPII
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
Q27
8H
CA
G→
CA
TFu
sion
/Bin
ding
Inhi
bito
rD
S(d
extr
ansu
lpha
te)
Sele
cted
Y?
V3
loop
regi
on;
S113
N/S
134N
/K26
9E/Q
278E
/
N29
3D/N
323S
/R38
7I:
250-
fold
Est
e97,
Est
e96a
Q27
8H
CA
G→
CA
TFu
sion
/Bin
ding
Inhi
bito
rJM
2763
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
10fo
ldSc
hols
98
Q27
8H
CA
G→
CA
TFu
sion
/Bin
ding
Inhi
bito
rJM
-276
3Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
Q27
8H
CA
G→
CA
CFu
sion
/Bin
ding
Inhi
bito
rJM
-276
3Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
122 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
Q27
8H
CA
G→
CA
CFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
Q27
8H
CA
G→
CA
TFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0C
ross
Res
ista
ntY
?10
6K/1
34N
/145
L/2
45I/
269E
/278
H/2
88V
/293
D/
364–
367D
elet
ion/
387T
:10
-fol
dSc
hols
98
Q27
8H
CA
G→
CA
TFu
sion
/Bin
ding
Inhi
bito
rM
ab12
G5
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
Scho
ls98
Q27
8H
CA
G→
CA
TFu
sion
/Bin
ding
Inhi
bito
rSD
F-1 α
Sele
cted
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
15-f
old.
Scho
ls98
Q27
8T
CA
G→
AC
GFu
sion
/Bin
ding
Inhi
bito
rA
LX
40–4
CC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
145-
fold
cros
s-re
sist
ant
toA
LX
40–4
C.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
Kan
bara
01
Q27
8T
CA
G→
AC
GFu
sion
/Bin
ding
Inhi
bito
rA
MD
3100
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)15
-fol
dcr
oss-
resi
stan
tto
AM
D31
00.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
Q27
8T
CA
G→
AC
GFu
sion
/Bin
ding
Inhi
bito
rSD
F-1
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)26
-fol
dcr
oss-
resi
stan
tto
SDF-
1.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
Q27
8T
CA
G→
AC
GFu
sion
/Bin
ding
Inhi
bito
rT
134
Sele
cted
YN
Invi
tro
sele
cted
viru
s(p
145
ofH
IV-1
NL
4–3,
cont
ains
mut
atio
nsN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5in
V3
loop
ofgp
120
)15
-fol
dre
sist
ant
to
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
Drug Resistance Mutations in HIV-1 Env 123
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
Q27
8T
CA
G→
AC
GFu
sion
/Bin
ding
Inhi
bito
rT
140
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)21
-fol
dcr
oss-
resi
stan
tto
T14
0.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
Q27
8T
CA
G→
AC
GFu
sion
/Bin
ding
Inhi
bito
rvM
IP-I
IC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
42-f
old
cros
s-re
sist
ant
tovM
IPII
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
R27
9K
Fusi
on/B
indi
ngIn
hibi
tor
AL
X40
–4C
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)14
5-fo
ldcr
oss-
resi
stan
tto
AL
X40
–4C
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
m
Kan
bara
01
R27
9K
Fusi
on/B
indi
ngIn
hibi
tor
AM
D31
00C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
15-f
old
cros
s-re
sist
ant
toA
MD
3100
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
R27
9K
Fusi
on/B
indi
ngIn
hibi
tor
SDF-
1C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
26-f
old
cros
s-re
sist
ant
toSD
F-1.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
R27
9K
Fusi
on/B
indi
ngIn
hibi
tor
T13
4Se
lect
edY
NIn
vitr
ose
lect
edvi
rus
(p14
5of
HIV
-1N
L4–
3,co
ntai
nsm
utat
ions
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275
inV
3lo
opof
gp12
0)
15-f
old
resi
stan
tto
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
124 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
R27
9K
Fusi
on/B
indi
ngIn
hibi
tor
T14
0C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
21-f
old
cros
s-re
sist
ant
toT
140.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
R27
9K
Fusi
on/B
indi
ngIn
hibi
tor
vMIP
-II
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)42
-fol
dcr
oss-
resi
stan
tto
vMIP
II.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
A28
4V
Fusi
on/B
indi
ngIn
hibi
tor
AL
X40
–4C
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)14
5-fo
ldcr
oss-
resi
stan
tto
AL
X40
–4C
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
m
Kan
bara
01
A28
4V
Fusi
on/B
indi
ngIn
hibi
tor
AM
D31
00C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
15-f
old
cros
s-re
sist
ant
toA
MD
3100
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
A28
4V
Fusi
on/B
indi
ngIn
hibi
tor
SDF-
1C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
26-f
old
cros
s-re
sist
ant
toSD
F-1.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
A28
4V
Fusi
on/B
indi
ngIn
hibi
tor
T13
4Se
lect
edY
NIn
vitr
ose
lect
edvi
rus
(p14
5of
HIV
-1N
L4–
3,co
ntai
nsm
utat
ions
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275
inV
3lo
opof
gp12
0)
15-f
old
resi
stan
tto
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
Drug Resistance Mutations in HIV-1 Env 125
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
A28
4V
Fusi
on/B
indi
ngIn
hibi
tor
T14
0C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
21-f
old
cros
s-re
sist
ant
toT
140.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
A28
4V
Fusi
on/B
indi
ngIn
hibi
tor
vMIP
-II
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)42
-fol
dcr
oss-
resi
stan
tto
vMIP
II.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
F28
5L
Fusi
on/B
indi
ngIn
hibi
tor
AL
X40
–4C
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)14
5-fo
ldcr
oss-
resi
stan
tto
AL
X40
–4C
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
m
Kan
bara
01
F28
5L
Fusi
on/B
indi
ngIn
hibi
tor
AM
D31
00C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
15-f
old
cros
s-re
sist
ant
toA
MD
3100
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
F28
5L
Fusi
on/B
indi
ngIn
hibi
tor
SDF-
1C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
26-f
old
cros
s-re
sist
ant
toSD
F-1.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
F28
5L
Fusi
on/B
indi
ngIn
hibi
tor
T13
4Se
lect
edY
NIn
vitr
ose
lect
edvi
rus
(p14
5of
HIV
-1N
L4–
3,co
ntai
nsm
utat
ions
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275
inV
3lo
opof
gp12
0)
15-f
old
resi
stan
tto
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
126 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
F28
5L
Fusi
on/B
indi
ngIn
hibi
tor
T14
0C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
21-f
old
cros
s-re
sist
ant
toT
140.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
F28
5L
Fusi
on/B
indi
ngIn
hibi
tor
vMIP
-II
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)42
-fol
dcr
oss-
resi
stan
tto
vMIP
II.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
V28
6Y
Fusi
on/B
indi
ngIn
hibi
tor
AL
X40
–4C
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)14
5-fo
ldcr
oss-
resi
stan
tto
AL
X40
–4C
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
m
Kan
bara
01
V28
6Y
Fusi
on/B
indi
ngIn
hibi
tor
AM
D31
00C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
15-f
old
cros
s-re
sist
ant
toA
MD
3100
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
V28
6Y
Fusi
on/B
indi
ngIn
hibi
tor
SDF-
1C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
26-f
old
cros
s-re
sist
ant
toSD
F-1.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
V28
6Y
Fusi
on/B
indi
ngIn
hibi
tor
T13
4Se
lect
edY
NIn
vitr
ose
lect
edvi
rus
(p14
5of
HIV
-1N
L4–
3,co
ntai
nsm
utat
ions
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275
inV
3lo
opof
gp12
0)
15-f
old
resi
stan
tto
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
Drug Resistance Mutations in HIV-1 Env 127
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
V28
6Y
Fusi
on/B
indi
ngIn
hibi
tor
T14
0C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
21-f
old
cros
s-re
sist
ant
toT
140.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
V28
6Y
Fusi
on/B
indi
ngIn
hibi
tor
vMIP
-II
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)42
-fol
dcr
oss-
resi
stan
tto
vMIP
II.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
I28
8T
ATA→
AC
AFu
sion
/Bin
ding
Inhi
bito
rA
LX
40–4
CC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
145-
fold
cros
s-re
sist
ant
toA
LX
40–4
C.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
Kan
bara
01
I28
8T
ATA→
AC
AFu
sion
/Bin
ding
Inhi
bito
rA
MD
3100
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)15
-fol
dcr
oss-
resi
stan
tto
AM
D31
00.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
I28
8T
ATA→
AC
AFu
sion
/Bin
ding
Inhi
bito
rSD
F-1
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)26
-fol
dcr
oss-
resi
stan
tto
SDF-
1.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
I28
8T
ATA→
AC
AFu
sion
/Bin
ding
Inhi
bito
rT
134
Sele
cted
YN
Invi
tro
sele
cted
viru
s(p
145
ofH
IV-1
NL
4–3,
cont
ains
mut
atio
nsN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5in
V3
loop
ofgp
120
)15
-fol
dre
sist
ant
to
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
128 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
I28
8T
ATA→
AC
AFu
sion
/Bin
ding
Inhi
bito
rT
140
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)21
-fol
dcr
oss-
resi
stan
tto
T14
0.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
I28
8T
ATA→
AC
AFu
sion
/Bin
ding
Inhi
bito
rvM
IP-I
IC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
42-f
old
cros
s-re
sist
ant
tovM
IPII
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
I28
8V
ATA→
GT
CFu
sion
/Bin
ding
Inhi
bito
rJM
2763
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
10fo
ldSc
hols
98
I28
8V
ATA→
GTA
Fusi
on/B
indi
ngIn
hibi
tor
JM-2
763
Sele
cted
Y?
Com
bina
tion
ofm
utat
ions
DeV
rees
e96a
I28
8V
ATA→
GTA
Fusi
on/B
indi
ngIn
hibi
tor
JM-3
100
Sele
cted
Y?
DeV
rees
e96,
DeV
rees
e96a
I28
8V
ATA→
GT
CFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0C
ross
Res
ista
ntY
?10
6K/1
34N
/145
L/2
45I/
269E
/278
H/2
88V
/293
D/
364–
367D
elet
ion/
387T
:10
-fol
dSc
hols
98
I28
8V
ATA→
GT
CFu
sion
/Bin
ding
Inhi
bito
rM
ab12
G5
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
Scho
ls98
I28
8V
ATA→
GT
CFu
sion
/Bin
ding
Inhi
bito
rSD
F-1α
Sele
cted
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
15-f
old.
Scho
ls98
ins
290
TFu
sion
/Bin
ding
Inhi
bito
rA
LX
40–4
CC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
145-
fold
cros
s-re
sist
ant
toA
LX
40–4
C.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
Kan
bara
01
ins
290
TFu
sion
/Bin
ding
Inhi
bito
rA
MD
3100
Sele
cted
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)15
-fol
dcr
oss-
resi
stan
tto
AM
D31
00.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
Drug Resistance Mutations in HIV-1 Env 129
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
ins
290
TFu
sion
/Bin
ding
Inhi
bito
rSD
F-1
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)26
-fol
dcr
oss-
resi
stan
tto
SDF-
1.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
ins
290
TFu
sion
/Bin
ding
Inhi
bito
rT
134
Cro
ssR
esis
tant
YN
Invi
tro
sele
cted
viru
s(p
145
ofH
IV-1
NL
4–3,
cont
ains
mut
atio
nsN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5in
V3
loop
ofgp
120
)15
-fol
dre
sist
ant
to
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
ins
290
TFu
sion
/Bin
ding
Inhi
bito
rT
140
Sele
cted
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)21
-fol
dcr
oss-
resi
stan
tto
T14
0.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
ins
290
TFu
sion
/Bin
ding
Inhi
bito
rvM
IP-I
IC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
42-f
old
cros
s-re
sist
ant
tovM
IPII
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
K29
0E
Fusi
on/B
indi
ngIn
hibi
tor
AL
X40
–4C
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)14
5-fo
ldcr
oss-
resi
stan
tto
AL
X40
–4C
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
m
Kan
bara
01
K29
0E
Fusi
on/B
indi
ngIn
hibi
tor
AM
D31
00C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
15-f
old
cros
s-re
sist
ant
toA
MD
3100
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
130 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
K29
0E
Fusi
on/B
indi
ngIn
hibi
tor
SDF-
1C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
26-f
old
cros
s-re
sist
ant
toSD
F-1.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
K29
0E
Fusi
on/B
indi
ngIn
hibi
tor
T13
4C
ross
Res
ista
ntY
NIn
vitr
ose
lect
edvi
rus
(p14
5of
HIV
-1N
L4–
3,co
ntai
nsm
utat
ions
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275
inV
3lo
opof
gp12
0)
15-f
old
resi
stan
tto
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
K29
0E
Fusi
on/B
indi
ngIn
hibi
tor
T14
0C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
21-f
old
cros
s-re
sist
ant
toT
140.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
K29
0E
Fusi
on/B
indi
ngIn
hibi
tor
vMIP
-II
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)42
-fol
dcr
oss-
resi
stan
tto
vMIP
II.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rA
LX
40–4
CC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
145-
fold
cros
s-re
sist
ant
toA
LX
40–4
C.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
Kan
bara
01
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rA
MD
3100
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)15
-fol
dcr
oss-
resi
stan
tto
AM
D31
00.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
Drug Resistance Mutations in HIV-1 Env 131
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rD
S(d
extr
ansu
lpha
te)
Sele
cted
Y?
V3
loop
regi
on;
S113
N/S
134N
/K26
9E/Q
278E
/
N29
3D/N
323S
/R38
7I:
250-
fold
Est
e97,
Est
e96a
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rJM
2763
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
10fo
ldSc
hols
98
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0C
ross
Res
ista
ntY
?10
6K/1
34N
/145
L/2
45I/
269E
/278
H/2
88V
/293
D/
364–
367D
elet
ion/
387T
:10
-fol
dSc
hols
98
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rM
ab12
G5
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
Scho
ls98
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rSD
F-1
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)26
-fol
dcr
oss-
resi
stan
tto
SDF-
1.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rSD
F-1 α
Sele
cted
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
15-f
old.
Scho
ls98
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rT
134
Sele
cted
YN
Invi
tro
sele
cted
viru
s(p
145
ofH
IV-1
NL
4–3,
cont
ains
mut
atio
nsN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5in
V3
loop
ofgp
120
)15
-fol
dre
sist
ant
to
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rT
140
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)21
-fol
dcr
oss-
resi
stan
tto
T14
0.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
N29
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rvM
IP-I
IC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
42-f
old
cros
s-re
sist
ant
tovM
IPII
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
N29
3H
AA
T→
CA
TFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
132 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
M29
4I
AT
G→
AT
CFu
sion
/Bin
ding
Inhi
bito
rA
LX
40–4
CC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
145-
fold
cros
s-re
sist
ant
toA
LX
40–4
C.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
Kan
bara
01
M29
4I
AT
G→
AT
CFu
sion
/Bin
ding
Inhi
bito
rA
MD
3100
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)15
-fol
dcr
oss-
resi
stan
tto
AM
D31
00.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
M29
4I
AT
G→
AT
CFu
sion
/Bin
ding
Inhi
bito
rSD
F-1
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)26
-fol
dcr
oss-
resi
stan
tto
SDF-
1.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
M29
4I
AT
G→
AT
CFu
sion
/Bin
ding
Inhi
bito
rT
134
Sele
cted
YN
Invi
tro
sele
cted
viru
s(p
145
ofH
IV-1
NL
4–3,
cont
ains
mut
atio
nsN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5in
V3
loop
ofgp
120
)15
-fol
dre
sist
ant
to
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
M29
4I
AT
G→
AT
CFu
sion
/Bin
ding
Inhi
bito
rT
140
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)21
-fol
dcr
oss-
resi
stan
tto
T14
0.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
ag
Kan
bara
01
M29
4I
AT
G→
AT
CFu
sion
/Bin
ding
Inhi
bito
rvM
IP-I
IC
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
42-f
old
cros
s-re
sist
ant
tovM
IPII
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
Drug Resistance Mutations in HIV-1 Env 133
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
Q29
6K
Fusi
on/B
indi
ngIn
hibi
tor
AL
X40
–4C
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)14
5-fo
ldcr
oss-
resi
stan
tto
AL
X40
–4C
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
m
Kan
bara
01
Q29
6K
Fusi
on/B
indi
ngIn
hibi
tor
AM
D31
00C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
15-f
old
cros
s-re
sist
ant
toA
MD
3100
.R
ole
ofea
chm
utat
ion
not
confi
rmed
bysi
te-d
irec
ted
mut
Kan
bara
01
Q29
6K
Fusi
on/B
indi
ngIn
hibi
tor
SDF-
1C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
26-f
old
cros
s-re
sist
ant
toSD
F-1.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
Q29
6K
Fusi
on/B
indi
ngIn
hibi
tor
T13
4Se
lect
edY
NIn
vitr
ose
lect
edvi
rus
(p14
5of
HIV
-1N
L4–
3,co
ntai
nsm
utat
ions
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275
inV
3lo
opof
gp12
0)
15-f
old
resi
stan
tto
T13
4.R
ole
ofea
chm
utat
ion
not
conf
Kan
bara
01
Q29
6K
Fusi
on/B
indi
ngIn
hibi
tor
T14
0C
ross
Res
ista
ntY
NT
134-
resi
stan
tvi
rus
(sel
ecte
din
vitr
o,co
n-ta
ins
N26
9K,
Q27
8T,
R27
9K,
A28
4V,
F285
L,
V28
6Y,
I288
T,K
290E
,N
293D
,M
294I
,an
dQ
296K
;29
0Tin
s,D
274–
275)
21-f
old
cros
s-re
sist
ant
toT
140.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
utag
Kan
bara
01
Q29
6K
Fusi
on/B
indi
ngIn
hibi
tor
vMIP
-II
Cro
ssR
esis
tant
YN
T13
4-re
sist
ant
viru
s(s
elec
ted
invi
tro,
con-
tain
sN
269K
,Q
278T
,R
279K
,A
284V
,F2
85L
,V
286Y
,I2
88T,
K29
0E,
N29
3D,
M29
4I,
and
Q29
6K;
290T
ins,
D27
4–27
5)42
-fol
dcr
oss-
resi
stan
tto
vMIP
II.
Rol
eof
each
mut
atio
nno
tco
nfirm
edby
site
-dir
ecte
dm
ut
Kan
bara
01
134 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
A29
7T
GC
A→
AC
AFu
sion
/Bin
ding
Inhi
bito
rJM
-276
3Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
N30
2K
AA
Aen
try
inhi
bito
rC
onca
nava
linA
(Con
A)
Sele
cted
Y?
mut
atio
nsin
gp12
0W
itvro
uw05
N30
2K
AA
Aen
try
inhi
bito
rC
yano
viri
n(C
V-N
)Se
lect
edY
?m
utat
ions
ingp
120
Witv
rouw
05
H30
8P
Fusi
on/B
indi
ngIn
hibi
tor
AD
101
Sele
cted
Y?
Smal
lm
olec
ule
entr
yin
hibi
tor.
Mut
atio
nin
gp12
0V3.
Prim
ary
R5
isol
ate,
CC
1/85
pas-
sage
din
PMB
Cin
incr
easi
ngco
ncen
trat
ions
ofC
CR
5-in
hibi
tor
AD
101.
Whe
nte
sted
inco
mbi
natio
nw
ithK
305R
,H
308P
,A
316V
and
G32
1E,
fold
-Rw
as>5×
106
Kuh
man
n04,
Trk
ola0
2
T31
1I
entr
yin
hibi
tor
Con
cana
valin
A(C
onA
)Se
lect
edY
?m
utat
ions
ingp
120
Witv
rouw
05
N32
3S
AA
T→
AG
TFu
sion
/Bin
ding
Inhi
bito
rD
S(d
extr
ansu
lpha
te)
Sele
cted
Y?
C3
regi
on;
S113
N/S
134N
/K26
9E/Q
278E
/
N29
3D/N
323S
/R38
7I:
250-
fold
Est
e97,
Est
e96a
G33
2E
GG
A→
GA
AFu
sion
/Bin
ding
Inhi
bito
rsi
amyc
inI
Sele
cted
Y?
N18
8K/G
332E
/N35
1D/A
550T
/N63
3D/L
762S
:9-
fold
Lin
96
I33
9T
AT
T→
AC
TFu
sion
/Bin
ding
Inhi
bito
rN
eoR
6Se
lect
edY
?M
utat
ion
ingp
120.
Foun
din
com
bina
tion
with
S372
L,
Q39
5K,
S668
R,
F672
Y.
Bor
kow
03
I33
9T
AT
T→
AC
TFu
sion
/Bin
ding
Inhi
bito
rR
3GC
ross
-RY
?M
utat
ion
ingp
120.
Test
edag
ains
tN
eoR
6-re
sist
ant
viru
spa
ssag
edin
vitr
o.V
irus
con-
tain
sm
utat
ions
I339
T,S3
72L
,Q
395K
,S6
68R
and
F672
Y.
Bor
kow
03
N35
1D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rsi
amyc
inI
Sele
cted
Y?
N18
8K/G
332E
/N35
1D/A
550T
/N63
3D/L
762S
:9-
fold
Lin
96
S37
2L
TC
A→
TTA
Fusi
on/B
indi
ngIn
hibi
tor
Neo
R6
Sele
cted
Y?
Mut
atio
nin
gp12
0.Fo
und
inco
mbi
natio
nw
ith
I339
T,Q
395K
,S6
68R
,F6
72Y
.
Bor
kow
03
S37
2L
TC
A→
TTA
Fusi
on/B
indi
ngIn
hibi
tor
R3G
Cro
ss-R
Y?
Mut
atio
nin
gp12
0.Te
sted
agai
nst
Neo
R6-
resi
stan
tvi
rus
pass
aged
invi
tro.
Vir
usco
n-ta
ins
mut
atio
nsI3
39T,
S372
L,
Q39
5K,
S668
Ran
dF6
72Y
.
Bor
kow
03
S37
5W
Fusi
on/B
indi
ngIn
hibi
tor
BM
S-48
8043
Sele
cted
Y?
Mut
atio
nin
CD
4co
ntac
tsi
te.
Lin
03
R37
8T
AG
A→
AC
AFu
sion
/Bin
ding
Inhi
bito
rJM
2763
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
10fo
ldSc
hols
98
R37
8T
AG
A→
AC
AFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0C
ross
Res
ista
ntY
?10
6K/1
34N
/145
L/2
45I/
269E
/278
H/2
88V
/293
D/
364–
367D
elet
ion/
387T
:10
-fol
dSc
hols
98
Drug Resistance Mutations in HIV-1 Env 135
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
R37
8T
AG
A→
AC
AFu
sion
/Bin
ding
Inhi
bito
rM
ab12
G5
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
Scho
ls98
R37
8T
AG
A→
AC
AFu
sion
/Bin
ding
Inhi
bito
rSD
F-1α
Sele
cted
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
15-f
old.
Scho
ls98
P38
5L
CC
A→
CTA
Fusi
on/B
indi
ngIn
hibi
tor
JM-2
763
Sele
cted
Y?
DeV
rees
e96,
DeV
rees
e96a
P38
5L
CC
A→
CTA
Fusi
on/B
indi
ngIn
hibi
tor
JM-3
100
Sele
cted
Y?
DeV
rees
e96,
DeV
rees
e96a
R38
7I
AG
A→
AC
AFu
sion
/Bin
ding
Inhi
bito
rD
S(d
extr
ansu
lpha
te)
Sele
cted
Y?
CD
4bi
ndin
gre
gion
;S1
13N
/S13
4N/K
269E
/
Q27
8E/N
293D
/N32
3S/R
387I
:25
0-fo
ld
Est
e97,
Est
e96a
Q39
5K
CA
G→
AA
GFu
sion
/Bin
ding
Inhi
bito
rN
eoR
6Se
lect
edY
?M
utat
ion
ingp
120
Foun
din
com
bina
tion
with
I339
T,S3
72L
,S6
68R
,F6
72Y
.
Bor
kow
03
Q39
5K
CA
G→
AA
GFu
sion
/Bin
ding
Inhi
bito
rR
3GC
ross
-RY
?M
utat
ion
ingp
120.
Test
edag
ains
tN
eoR
6-re
sist
ant
viru
spa
ssag
edin
vitr
o.V
irus
con-
tain
sm
utat
ions
I339
T,S3
72L
,Q
395K
,S6
68R
and
F672
Y.
Bor
kow
03
Q41
0E
CA
A→
GA
AFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
N41
8S
entr
yin
hibi
tor
Cya
novi
rin
(CV
-N)
Sele
cted
Y?
mut
atio
nsin
gp12
0W
itvro
uw05
M42
6L
AT
G→
TT
GFu
sion
/Bin
ding
Inhi
bito
rB
MS-
4880
43Se
lect
edY
?M
utat
ion
ingp
120.
Lin
04,
Lin
03
W42
7V
Fusi
on/B
indi
ngIn
hibi
tor
BM
S-48
8043
Sele
cted
Y?
Mut
atio
nin
CD
4co
ntac
tsi
te.
Lin
03
S43
3P
TC
C→
CC
CFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0Se
lect
edY
?D
eVre
ese9
6,D
eVre
ese9
6a
M43
4I
AT
G→
?Fu
sion
/Bin
ding
Inhi
bito
rB
MS-
4880
43Se
lect
edY
?M
utat
ion
ingp
120.
Lin
04,
Lin
03
S44
0R
Fusi
on/B
indi
ngIn
hibi
tor
BM
S-48
8043
Sele
cted
Y?
Mut
atio
nin
gp12
0.L
in03
V45
7I
GTA→
ATA
Fusi
on/B
indi
ngIn
hibi
tor
JM-3
100
Sele
cted
Y?
DeV
rees
e96,
DeV
rees
e96a
M47
5I
AT
G→
?Fu
sion
/Bin
ding
Inhi
bito
rB
MS-
4880
43Se
lect
edY
?M
utat
ion
ingp
120.
Lin
04,
Lin
03
A55
0T
GC
C→
AC
CFu
sion
/Bin
ding
Inhi
bito
rsi
amyc
inI
Sele
cted
Y?
N18
8K/G
332E
/N35
1D/A
550T
/N63
3D/L
762S
:9-
fold
Lin
96
Q57
4R
Ent
ryIn
hibi
tor
Ret
rocy
clin
-101
(RC
-
101)
Sele
cted
YSu
bstit
utio
nin
gp16
0at
posi
tion
574,
corr
e-
spon
ding
toth
eH
R1
dom
ain
ofgp
41
Col
e06
N63
3D
AA
T→
GA
TFu
sion
/Bin
ding
Inhi
bito
rsi
amyc
inI
Sele
cted
Y?
N18
8K/G
332E
/N35
1D/A
550T
/N63
3D/L
762S
:9-
fold
Lin
96
S66
8R
AG
T→
AG
AFu
sion
/Bin
ding
Inhi
bito
rN
eoR
6Se
lect
edY
?M
utat
ion
ingp
41.
Foun
din
com
bina
tion
with
I339
T,S3
72L
,Q
395K
,F6
72Y
.
Bor
kow
03
S66
8R
AG
T→
AG
AFu
sion
/Bin
ding
Inhi
bito
rR
3GC
ross
-RY
?M
utat
ion
ingp
41.
Test
edag
ains
tN
eoR
6-re
sist
ant
viru
spa
ssag
edin
vitr
o.V
irus
con-
tain
sm
utat
ions
I339
T,S3
72L
,Q
395K
,S6
68R
and
F672
Y.
Bor
kow
03
136 Drug Resistance Mutations in HIV-1 Env
HIV
-1E
nv
Am
ino
Aci
dC
odon
Dru
gSe
lect
edIn
In
Cha
nge
Cha
nge
Cla
ssC
ompo
und
orC
ross
-Rvi
tro
vivo
Com
men
tsR
efs
F67
2Y
TT
T→
TAT
Fusi
on/B
indi
ngIn
hibi
tor
Neo
R6
Sele
cted
Y?
Mut
atio
nin
gp41
.Fo
und
inco
mbi
natio
nw
ith
I339
T,S3
72L
,Q
395K
,S6
68R
.
Bor
kow
03
F67
2Y
TT
T→
TAT
Fusi
on/B
indi
ngIn
hibi
tor
R3G
Cro
ss-R
Y?
Mut
atio
nin
gp41
.Te
sted
agai
nst
Neo
R6-
resi
stan
tvi
rus
pass
aged
invi
tro.
Vir
usco
n-ta
ins
mut
atio
nsI3
39T,
S372
L,
Q39
5K,
S668
Ran
dF6
72Y
.
Bor
kow
03
L76
2S
TT
G→
TC
GFu
sion
/Bin
ding
Inhi
bito
rsi
amyc
inI
Sele
cted
Y?
N18
8K/G
332E
/N35
1D/A
550T
/N63
3D/L
762S
:9-
fold
Lin
96
FNST
W36
4–36
8D
elet
ion
TT
TA
AT
AG
TA
CT
TG
GFu
sion
/Bin
ding
Inhi
bito
rD
S(d
extr
ansu
lpha
te)
Sele
cted
YE
ste9
7
FNST
W36
4–36
8D
elet
ion
Del
etio
nFu
sion
/Bin
ding
Inhi
bito
rJM
2763
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
10fo
ldSc
hols
98
FNST
W36
4–36
8D
elet
ion
Del
etio
nFu
sion
/Bin
ding
Inhi
bito
rJM
-310
0C
ross
Res
ista
ntY
?10
6K/1
34N
/145
L/2
45I/
269E
/278
H/2
88V
/293
D/
364–
367D
elet
ion/
387T
:10
-fol
dSc
hols
98
FNST
W36
4–36
8D
elet
ion
Del
etio
nFu
sion
/Bin
ding
Inhi
bito
rM
ab12
G5
Cro
ssR
esis
tant
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
Scho
ls98
FNST
W36
4–36
8D
elet
ion
Del
etio
nFu
sion
/Bin
ding
Inhi
bito
rSD
F-1 α
Sele
cted
Y?
106K
/134
N/1
45L
/245
I/26
9E/2
78H
/288
V/2
93D
/36
4–36
7Del
etio
n/38
7T:
15-f
old.
Scho
ls98
dele
tion
364–
376
entr
yin
hibi
tor
Cya
novi
rin
(CV
-N)
Sele
cted
Y?
mut
atio
nsin
gp12
0W
itvro
uw05
Abbreviations/Compounds 137
Abbreviations used in tablesAmino acids Drug classA alanine F/BI Fusion/Binding InhibitorC cysteine II Integrase InhibitorD aspartate MN Multiple NucleosideE glutamate NRTI Nucleoside Reverse Transcriptase InhibitorF phenyalanine NNRTI HIV-1 Specific Nonnucleoside RT InhibitorG glycine PI Protease InhibitorH histidine PARTI Pyrophosphate Analogue RTII isoleucine SIV RTI SIV Nucleoside RTIK lysineL leucineM methionineN asparagineP prolineQ glutamineR arginineS serineT threonineV valineW tryptophanY tyrosine
CompoundsOther Names Chemical Name
Compound (Company) or Description
(-)-dOTC BCH-10652 (-)-2′-deoxy-3′-oxa-4′-thiocytidine(-)-dOTFC (-)-2′-deoxy-3′-oxa-4′-thio-5-fluorocytidine(-)-FTC Emtricitabine,
Coviracil (TrianglePharmaceuticals)
(-)-(2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine
(+)-dOTC (+)-2′-deoxy-3′-oxa-4′-thiocytidine(+)-dOTFC (+)-2′-deoxy-3′-oxa-4′-thio-5-fluorocytidine1737 Tetrahydronapthalene lignan derivative1592U89 Abacavir, Ziagen, ABC
(Glaxo Wellcome)(1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate
3TC (-)-BCH-189, Lamivu-dine, Epivir (GlaxoWellcome)
(-)-β-L-2′,3′-dideoxy-3′-thiacytidine
4′-Ed4T 2′,3′-Didehydro-3′-deoxy-4′-ethynylthymidine8-chloro-TIBO RO91767, R86183,
tivirapine(+)-(S)-4,5,6,7-Tetrahydro-8-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazol[4,5,1-jk][1,4]benzodiazepine
A-77003 C2 symmetry-based pro-tease inhibitor (Abbott)
2PyridCH2NCH3CO-Val-NHCH(Bz)]CHOHCHOH
AAP-BHAP U-104489 (Pharmacia &Upjohn)
1-[(5-Methanesulfonamidoindol-2-yl)carbonyl]-4-[N-ethyl-N-[3-(1,1-dimethyl)amino]-2-pyridinyl]amino]piperidine
ABT-378 Aluviran, Lopinavir(Abbott)
N-[(1S,3S,4S)-4-[[2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-α-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide
ABT-538 Ritonovir, Norvir(Abbott)
10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester
138 Abbreviations/Compounds
Abbreviations (cont)
Compounds(cont)
AD101ADAMII Methyl 3′,3′′-dichloro-4′,4′′-dimethoxy-5′,5′′-
bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoateAG1343 Nelfinavir, Viracept
(Agouron)(3S,4aS,8aS)-N-tert-Butyl-2-[(2R,3R)-3-(3,2-cresotamido)-2-hydroxy-4-(phenylthio)butyl]decahydro-3-isoquinoline-carboxamide monomethanesulfonate
ALX40-4C a polypeptide of nine d-Arg residuesAMD3100 octahydrochloride dihydrate of 1,19-[1,4-phenylene-bis-
(methylene)]-bis-1,4,8,11-tetra-azacyclotetradecaneAmphotericin BMethyl Ester
[2-[[(4E,6E,8E,10E,12E,14E,16E)-38-carboxy-19,25,27,30,31,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10,12,14,16-heptaen-3-yl]oxy]-3,5-dihydroxy-6-methyl-oxan-4-yl]azanium chloride
AZT zidovudine (GlaxoWellcome)
3′-azido-3′-deoxythymidine
BHAP U-87201E Atevirdine (PharmaciaUpjohn)
1-[(5-Methyoxyindol-2-yl)carbonyl]-4-[3-(ethylamino)-2-pyridyl]piperazine
BHAP U-88204E 1-(Indolyl-2-carbonyl)-4-[3-[(1-methylethyl)amino]pyridyl-piperazine
BHAP U-90152 Delavirdine, Rescriptor(Pharmacia Upjohn)
1-(5-Methanesulphonamido)-1H-indol-2-yl-carbonyl)-4-[3-(isopropylamino)-2-pyridinyl]piperazine
BHAP U-90153 bisheteroarylpiperidinyl derivativeBHAP U-90154 bisheteroarylpiperidinyl derivativeBHAP U-90155 bisheteroarylpiperidinyl derivativeBILA 1906 BS (Bio-Mega/Boehringer
Ingelheim)N-{1S-[[[3-[2S-(1,1-dimethylethyl)amino]carbonyl-4R-]3-pyridinylmethyl)thio]-1-piperidinyl]-2R-hydroxy-1S-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl}-2-quinolinecarboxamide
BILA 2011 Palinavir (Bio-Mega/BoehringerIngelheim)
N-{1S-[[[3-[2S-(1,1-dimethylethyl)amino]carbonyl]-4R-[4-pyridinylmethyl)oxy]-1-piperidinyl]-2R-hydroxy-1S-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl}-2-quinolinecarboxamide
BILA 2185 BS (Bio-Mega/BoehringerIngelheim)
N-(1,1-dimethylethyl)-1-[2S-[[2-2,6-dimethyphenoxy)-1-oxoethyl]amino]-2R-hydroxy-4-phenylbutyl]4R-pyridinylthio)-2-piperidine-carboxamide
BI-RG-587 Nevaripine, Viramune(Boehringer Ingleheim)
11-Cyclopropyl-4-methyl-5,11-dihydro-6H-dipyrido[3,2-b:2′,3′-e]-[1,4]diazepin-6-one
BM+51.0836 thiazolo-isoindolinone derivativeBMS-186318 (Bristol-Myers Squibb) [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)-
carbonyl]amino]-2-hydroxy-4-[4-[2-(4-morpholinyl)-2-oxoethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic Acid, 1,1-dimethylethyl-ester
BMS-232632 Atazanavir azapeptide protease inhibitorBMS-488043Calanolide A NSC675451 a dipyranocoumarinConcanavalin A ConA plant lectin from Canavalia ensiformisCyanovirin CV-N, NSC 682999 (Cel-
legy Pharmaceuticals)Protein from cyanobacterium Nostoc ellipsosporum
Abbreviations/Compounds 139
Abbreviations (cont)
Compounds (cont)
cyclo-d4G β-D-6-cyclopropylamino-2′,3′-Didehydro-2′3′-Dideoxyguanosine
d-d4FC D4FC, DPC 187 2′3′-Didehydro-2′ 3′ dideoxy -5-fluorocytidined4C Didehydro-2′ 3′ dideoxy cytidined4T Stavudine, Zerit (Bristol-
Myers Squibb)2′,3′-didehydro-3′-deoxythymidine
ddC Zalcitabine, Hivid(Roche)
2′,3′-dideoxycytidine
ddI Didanosine, Videx(Bristol-Myers Squibb)
2′,3′-dideoxyinosine
DihydroxythiopheneDKA beta-diketo acidsDMP-266 Efavirenz, Sustiva
(Dupont Merck)(-)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4,-dihydro-2H-3,1-benzoxazin-one
DMP-323 XM-323 (Dupont Merck) [4R-(4-α,5-α,6-β,7-β)]-hexahydro-5,6-dihydroxy-1,3-bis[(4-hydroxymethyl)phenyl]methyl]-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one
DMP-450 (Avid Therapeutics) [4R-(4-α,5-α,6-β,7-β)]-hexahydro-5,6-bis(hydroxy)-1,3-bis(3-amino)phenyl]methyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-onebismesylate
(+)dOTFC (+)-dOTFC (+)-2′-Deoxy-3′-oxa-4′-thio-5′-fluorocytidineDS dextran sulfateDXG (-)-β-dioxolane-G (-)-(2R,4R)-9-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]guanineE-BPTU NSC 648400 1-benzyloxymethyl-5-ethyl-6-(2-pyridylthio)uracilEBU-dM 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracilE-EBU 5-ethyl-1-ethoxymethyl-6-benzyluracilE-EPSeU 1-(ethoxymethyl)-(6-phenylselenyl)-5-ethyluracilE-EPU 1-(ethoxymethyl)-(6-phenyl-thio)-5-ethyluracilF-ddA Lodenosine 2′-fluoro-2′,3′-dideoxyadenosineFZ41 styrylquinolineGW420867X S-3-ethyl-6-fluoro-4-isopropoxycarbonyl-3,4-dihydro-
quinoxalin-2(1H)-oneHBY 097 (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-
3,4-dihydroquinoxalin-2(1H)-thioneHEPT 1-[(2-hydroxyethoxy)methyl]6-(phenylthio)thymineIC9564 Betulinic acid derivative 4S-[8-(28 betuliniyl) aminooctanoylamino]-3R-hydroxy-6-
methylheptanoic acidI-EBU MKC-442, emivirine,
coactinon (TrianglePharmaceuticals)
6-benzyl-1-ethoxymethyl-5-isopropyluracil/
JE-2147 an allophenylnorstatine-containing dipeptide proteaseinhibitor
JM-2763 (Johnson Matthey) 1,10-(1,3-propanediyl)-bis-1,4,8,11-tetraazacyclo-tetradecaneJM-3100 SID791 (Johnson
Matthey)1,10-[1,4-phenylenebis-(methylene)]bis-(1,4,8,11-tetraazacyclotetradecane)octahydrochloride dihydrate
KNI-272 Kynostatin 272 (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid-containingtripeptide
L-697,593 5-ethyl-6-methyl-3-(2-phthalimido-ethyl)pyridin-2(1H)-oneL-697,661 3-[(-4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino-5-ethyl-
6-methylpyridin-2(1H)-oneL-Chicoric acid [S-(R*,R*)]-2,3-Bis[[3-(3,4-dihydroxyphenyl)-1-oxo-2-
propenyl]oxy]butanedioic acid
140 Abbreviations/Compounds
Abbreviations (cont)
Compounds (cont)
L-FddC (-)-β-L-5-fluoro-2′,3′-dideoxy-cytidineLY-300046 HCl Trovirdine
(Lilly/Medivir/Abbott)N-[2-(2-pyridylethyl)-N′-[2-(5-bromopyridyl)thiourea,hydro-chloride
M87 membrane anchored gp41 derived peptideMK-639 Indinavir, Crixivan,
L735,524 (Merck)[1(1S,2R),5(S)]-2,3,5-Trideoxy-N-(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D-erythro-pentonamide sulfate
MP-134 C2 symmetry-based protease inhibitorMP-167MSK-076 (Medivir AB) phenylmethylthiazolythiourea (PETT) derivativeNeoR6 hexa-arginine neomycin B
conjugateno name O-(2-Phenoxy ethyl)benzoyl
(phenyl) thiocarbamate 17cP-1946 methyl N-[(1S)-1-[[(5S)-5-[(4-aminophenyl)sulfonyl-(2-
methylpropyl)amino]-6-hydroxy-hexyl]carbamoyl]-2-(1H-indol-3-yl)ethyl]carbamate
P9941 (Dupont Merck) [2-pyridylacetyl-IIePheAla-y(CHOH)]2PA-457 Bevirimat (Panacos) 3-O-(3′, 3′−dimethylsuccinyl)betulinic acidPFA Foscarnet (Astra) phosphonoformateph-AZT 5′-phosphit 3′ azido-2′3′-
dideoxythymidinePMEA adefovir (Gilead
Sciences)9-(2 phosphonylmethoxyethyl)adenine
PMPA tenofovir (GileadSciences)
(R)-9-(2-phosphonyl-methoxypropyl)adenine
PNU-140690 Tipranavir, U-140690(Pharmacia & Upjohn)
(6R)-3-(1R)-1-[3-([Trifluoromethyl)(2-pyridyl)]sulfonylamino)-phenyl]propyl-4-hydroxy-6-(2-phenylethyl)-6-propyl-5,6-dihydro-2H-pyran-2-one
QM96521 1,1,3-trioxo-2H,4H-thieno[2,4-3][1,2,4]thiadiazine derivative(TTD)
QYL-609QYL-685 methylenecyclopropane nucleoside analog with a phenylphos-
phoralaninate moietyR3G tri arginine gentamicin C conjugateRetrocyclin-101 18-aa peptide
GICRCICGKGICRCICGRRo 31-8959 Saquinavir, Invirase, For-
tovase (Roche)N(1)-[3-[3-[[(1,1-dimethylethyl)amino]carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-,[3S-[2[1R*(R*),2S*],3α,4aβ,8aβ]]-,monomethanesulfonate
RPI-312 1-[(3S)-3-(n-alpha-benzyloxycarbonyl)-l-asparginyl)-amino-2-hydroxy-4-phenyl-butyryl]-n-tert-butyl-l-proline amide (peptidylprotease inhibitor)
RPR103611 a triterpene betulinic acid derivativeRO033-4649 (Roche)S-1153 5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-
1Himidazol-2-yl methyl carbamateS-2720 6-chloro-3,3-dimethyl-4-(isopropenyl-oxycarbonyl)-3,4-
dihydroquinoxalin-2(1H)thione
Abbreviations/Compounds 141
Abbreviations (cont)
Compounds (cont)
SC-52151 Telinavir N-tert-butyl-N′-isobutyl-N′-[2(R)-hydroxy-4-phenyl-3(S)-[4-amino-1,4-dioxo-2(S)-(2-quinolinylcarboxamido)butyl-amino]butyl]urea
SC-55389A (Searle) hydroxyethyl-urea isostere protease inhibitorSDF-1 Stromal cell-derived factor 1SDF-1α Stromal cell-derived factor 1αSiamycin I 21-residue tricyclic peptideSKF108842 protease inhibitorT134 [Tyr5,12, Lys7]-polyphemusin II-derivative with amino acid
sequence R-R-W-C-Y-R-K-DK-P-Y-R-Ci-C-R-COOHT140 [Tyr5,12, Lys7]-polyphemusin II-derivativeT20 DP-178, Pentafuside
(Trimeris)Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2
TIBO R82150 (Janssen) (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione
TIBO R82913 (Janssen) (+)-(5S)-4,5,6,7,-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)-imidazo-[4,5,1-jk]-[1,4]benzo-diazepin-2(1H)-thione
TMC114 UIC-94017, Darunavir,Prezista (Tibotec)
[(1S,5R,8S)-4,6-dioxabicyclo[3.3.0]oct-8-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenyl-butan-2-yl]carbamate
TMC125TSAO [2′,5′-bis-O-(tert-butyldimethylsilyl)-3′-spiro-5′′-(4′′-
amino-1′′,2′′-oxathiole-2′′,2′′-dioxide)]-β-D-pentofuranosylderivative
UC-10 NSC 645129 (UniroyalChemical Co)
thiocarboxanilide derivative
UC-16 (Uniroyal Chemical Co) thiocarboxanilide derivativeUC-32 NSC 645542 (Uniroyal
Chemical Co)thiocarboxanilide derivative
UC-38 NSC 629243 (UniroyalChemical Co)
4-chloro-3-(isopropoxycarbonyl)phenylcarbamothioic acid,O-isopropyl ester
UC-42 (Uniroyal Chemical Co) thiocarboxanilide derivativeUC-57 NSC 647014 (Uniroyal
Chemical Co)thiocarboxanilide derivative
UC-68 NSC 638532 (UniroyalChemical Co)
thiocarboxanilide derivative
UC-69 NSC 646989 (UniroyalChemical Co)
thiocarboxanilide derivative
UC-70 NSC 638534 (UniroyalChemical Co)
thiocarboxanilide derivative
UC-80 NSC 639475 (UniroyalChemical Co)
thiocarboxanilide derivative
UC-81 NSC 615727 (UniroyalChemical Co)
thiocarboxanilide derivative
UC-82 (Uniroyal Chemical Co) N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-thiophenecarbothioamide
UC-84 NSC 615985 (UniroyalChemical Co)
thiocarboxanilide derivative
UC-581 NSC 645727 (UniroyalChemical Co)
UC-781 (Uniroyal Chemical Co) N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide
142 Abbreviations/Compounds
Abbreviations (cont)
Compounds (cont)
UCO40 NSC650065UIC-94003VB 11,328 (Vertex) Carbamic acid, [3-[[(4-methoxyphenyl)sulfonyl](cyclo-
pentylmethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-,tetrahydro-3-furanyl ester
vMIP-II viral macrophage inflammatory protein IIVRX-329747VX-478 141W94, Amprenavir,
AgeneraseCarbamic acid, ((1S,2R)-3-(((4-aminophenyl)sulfonyl)(2-methylpropyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-,(3S)-tetrahydro-3-furanyl ester
α-APA R18893, loviride analog (+)-2,6-Dichloro-α-[(2-acetyl-5-methylphenyl)amino]benzamide
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