The pathogenesis of persistent HIV-associated inflammation during long-term antiretroviral therapy
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Transcript of The pathogenesis of persistent HIV-associated inflammation during long-term antiretroviral therapy
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The pathogenesis of persistent HIV-associated inflammation
during long-term antiretroviral therapy
Steven G. DeeksProfessor of Medicine
University of California, San Francisco
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Untreated and to a lesser degree treated HIV infection is associated with increased frequency of “activated” (CD38+
HLA-DR+) T cells%
CD
38+H
LAD
R+
CD
8+ T
Cel
ls
0
20
40
60
80
HIVNegative(n=82)
Non-Controller
(n=65)
HAART(n=132)
P < 0.001
P < 0.001
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Activated CD38+ HLA-DR+ T cells are rapidly turning over in untreated disease
Srinivasula et al., Blood 2011
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Pre-treatment activation “set-point” strongly predicts extent of activation during
suppressive HAARART
Hunt et al, CROI 2010, Poster #306, and submitted
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UARTO: High CD8+ T aell activation at month 6 of HAART predicts mortality in Ugandans with VL<400
Hunt et al, CROI 2010, Poster #306, and submitted
In Cox Proportional Hazards models, each 10% increase in the frequency of activated (%CD38+ HLA-DR+) CD8+ T cells was associated with an increased hazard of death even after adjustment for
baseline CD4 count (HR: 1.62, P=0.048) or month 6 CD4 count (HR: 1.61, P=0.042).
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Why are “activated” T cells elevated in antiretroviral-treated disease?
• Residual HIV replication• CMV (and other prevalent co-infections)• Microbial translocation• Lack of immunoregutory responses• Thymic dysfunction and residual defects in
adaptive immune responses• Lymphoid fibrosis• Co-morbid conditions (metabolic syndrome,
central adiposity)
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Does residual replication during
HAART contribute to chronic inflammation?
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Slide #8Raltegravir intensification had no effect on CD8+ T cell activation (blood and GALT) suggesting that
active viral replication is not a causes of persistent inflammation
PBORGV
0 4 8 12 16 20 240
10
20
30
Weeks
% C
D38
+HLA
-DR
+C
D8+
T c
ells
(blo
od)
Hatano et al., JID 11
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Massanella et al., CROI 2011
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The size of HIV reservoir (as defined by RNA/DNA ratio) is associated with frequency of activated
CD4+ T cells in rectal tissues
Hatano, Hunt, Yukl and Wong (IAS 2011)
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Microbial translocation
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Most (but not all) studies have shown that HIV infection results in mucosal damage, microbial translocation and
inflammation; this effect persists during HAART
0
100
200
300
HIVNegative
HAARTVL < 75
Untreated
P = 0.002
P = 0.001Pl
asm
a LP
S (p
g/m
L)
Brenchley JM Nature Medicine 2006
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Levels of sCD14 (a marker of LPS and/or monocyte/macrophage activation) predicts
mortality in HIV disease independent of other factors (SMART study)
Sandler JID 2011
2.07-2.34
2.35-2.75
>2.75
<2.07x106 pg/ml
Univariate
Adjusted for IL-6, D-dimer, CRP, SAA and virus load
0 5 10 15 20 25
OR (95% CI)
sCD14: OR of Death by Quartile
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Chronic CMV Infection
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Sylwester/Picker, JEM, 2005
CMV elicits massive immune responses even in asymptomatic young HIV uninfected adults
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CMV-specific CD8 ResponsesBy HIVStatus
0
1
2
HIV-N=37
HIV+Untreated
N=102
HIV+HAART+
N=283
P<0.001
P<0.001
% p
p65-
spec
ific
IFN
- -pro
duci
ng C
D8+
T C
ells
CMV-specific T cell responses are approximately five fold higher in treated
HIV infected adults
Naeger et al, PLoS ONE 2009
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Higher CMV-specific CD8 IFN-γ production associated with atherosclerosis in several studies
Hsue et al, AIDS, 2006
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Loss of T cell regenerative capacity
and altered immunoregulatory
responses
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HIV-associated inflammation → T reg response → TGF-β → Collagen deposition → Fibrosis → Reduced IL-7 → Reduced T cell regeneration → Inflammation
CD3+
Collagen 1 +
Desmin +
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Inflammation increases IDO production which in turn causes Th17 depletion, microbial
translocation and more inflammation
IFN-γLPS
IDOInductionin DC/MØ
↓TryptophanT Cell
Proliferative Defect
MicrobialTranslocation
↑HAA Th17 Depletion
Favre/McCune Science Translationa Med 2010Hunt et al, IAS, 2011, #MOAA0105
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Telomeres and Telomerase
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Telomerase (a reverse transcriptase) is inhibited by certain NRTIs (ZDV, d4T, TDF), and treated HIV disease is associated
with shorter telomeres
Strahl and Blackburn. Nuc Acid Res 1994:22:893–900Leeansyah et al. 6th IAS on Pathogenesis, Clinical Research and Prevention, Rome, July 2011; Poster TUPE127
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Annu Rev Med 2011;62:141-55.
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Conclusions• T cell activation as defined by CD38 and HLA-DR
expression remains elevated during HAART• Functional characteristics of cells not fully defined
• T cell activation associated with disease• Multiple mechanisms cause activation during HAART
• Residual HIV replication (controversial)• Microbial translocation (controversial)• CMV and other co-pathogens (needs confirmation)• Loss of T regulatory cells and other immunoregulatory
responses• Lymphoid fibrosis (may be central to preceding causes)• Homeostatic proliferation (not “activation”)• Telomerase inhibition (indirect effect)• Metabolic syndrome, abdominal obesity
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AcknowledgementsElsewhereNetanya SanderDanny DouekMichael LedermanAlan LandayRussell TracyApril FerreBarbara ShacklettTim ShackerAshley HaaseLarry CoreyRobert KaplanSharon Lewin
SCOPE Cohort / UCSFPeter HuntHiroyu HatanoJeff Martin David NaegerRebecca HohRick HechtVivek JainElizabeth SinclairLorrie EplingMike McCune
NIAID RO1 AI087145,
K24AI069994, CNICS
(5R24AI067039), CLIC