Professor Brigitte Autran - Mediscript - Medical Publishers · D N H I V / M o d e c e l l u l e s....

16th Annual Resistance and Antiviral

Therapy Meeting

Professor Brigitte Autran 1

Thursday 20 September 2012, Wellcome Collection Conference Centre, London

Professor Brigitte AutranCentre Hospitalier Universitaire Pitié-Salpétrière,

Paris, France

16161616 thththth Annual Resistance Annual Resistance Annual Resistance Annual Resistance andandandandAntiviral Therapy MeetingAntiviral Therapy MeetingAntiviral Therapy MeetingAntiviral Therapy Meeting

How controlling HIV-1 reservoirs and strategies for

an HIV CureWhat is going to work?

Pr Brigitte AutranInst. of Researches Immunity, Cancer and Infection ,

Université Pierre et Marie Curie - Hôpital Pitié-Salpêtrière, France


Therapy Meeting


« Towards an HIV CURE »

Connecting researchers together

WHAT ELSE?WHAT ELSE?WHAT ELSE?WHAT ELSE?

A global scientific strategy defining research priorities

INTERNATIONAL ADVISORY BOARD

INTERNATIONAL SCIENTIFIC WORKING GROUP

Clinical Trials Basic Science

INTERNATIONAL CONSULTATIONS

Development Implementation

Launch

Workshop on towards a cure

F Barré-Sinoussi

• “resting cells hosting inducible integrated HIV-DNA” (Blankson 2002)

• Estimated life span: 69 years (Chomont 2009)

Half-life (days)

0 30 60 90 120 ?

Free VirionsFree Virions

Infected activated CD4 T cells producing HIVInfected activated CD4 T cells producing HIV

RestingResting CD4+ T CD4+ T cellscells harboringharboring HIV DNA HIV DNA ((integratedintegrated or not)or not)

Free Virions on Follicular dendritic cells Free Virions on Follicular dendritic cells (lymphoid tissues)(lymphoid tissues)

Infected MacrophagesInfected Macrophages(all tissues and sanctuaries)(all tissues and sanctuaries)

Resting CD4+ T cell Resting CD4+ T cell

harboring integrated HIVharboring integrated HIV--

DNADNA

CD4 T cells

Naive yearsTCM < 3-6 monthsTTM ?TEM 1-3 monthsEffector cells 8-15 days

Non T cells

Monocytes 1,5 weeks

Macrophages 3 months

(Siliciano 1999)

What is the HIV reservoir?


Therapy Meeting


HIV RESERVOIRS at various stages of HIV infection

UNTREATED

UN-TREATED10y HAART

Chronic

DecamuneDecamuneGuihot, AIDS

2010

UN-TREATED5-y HAARTPHI / PTC

HIV RESERVOIRS at various stages of the HIV infecti onEffect of early and long term ART

Data from the french ANRS Cohorts


Therapy Meeting


Proposed mechanisms of HIV persistence during HIV infection andtargeting for an HIV cure

Targeted by HIV-specific CTLs anti-latency agents

HAART =>

Immune recovery+ persisting anti-HIV

CD8 TCM

but decay in anti-HIV TEM

Limited lifespan of the HIV Immune Reservoirs :

Clues for

a Long Term Immune or a Therapeutic HIV control

CD4 T cell Life span

Naive CD4 Effector TCM Transitional TEM10 Years (?) (8-15 days) (> 3-6 mths) ? (1-3 mths)

Naive

CD4+cell

CD45RA

CC

R7

Apoptosis

Turnover

effectoreffectorEffector

CD4 T cells

CD45RA

CC

R7

memorymemory

Central

Memory

CD4 T cells

CD45RA

CC

R7

CD45RA

CC

R7

memorymemoryEffector

Memory

CD4 T cells

CD27

CC

R7 memory

memoryTransitionnal

CD4 T cells

Monocytes

Non T cellsMonocytes Macrophages1,5 week 3 months

Macrophages


Therapy Meeting


Rapid dissemination of HIV infection

HIV Reservoirs

Naive

CD4+cell

CD45RA

CC

R7

Apoptosis

Turnover


CD4 T

cellsCD45RA

CC

R7

memorymemoryCentral

Memory

CD4 T cellsCD45RA

CC

R7

CD45RA

CC

R7

memorymemory

Effector

Memory

CD4 T cells

CD27

CC

R7 memory

memoryTransitionnal

CD4 T cells

Peindre

Peindre

(Haase 2010)

= Irreversible integration of HIV-DNA in the cellular genome

Massive depletion of

CD4 cells

Description of the HIV reservoir

• Primary HIV infection (PHI):

- Mucosal TTM and TEM CD4 subsets from the gut lamina propria

(Rhesus Macaques)

- Integrated SIV-DNA in memory CD4+ T cells (1 copie/10 cells)

- Latently-infected CD4 cells 30 days from transmission

- Total TN, TCM, TTM and TEM infected 225 days from contamination

(Mattapallil 2005)

(Nishimura 2007)

(Chun 1998)

(Ganesan 2010)

(Chun 1997)

(Brenchley 2003)

(Chomont 2009)

• Chronic phase:

- Resting memory CD4 T cells (HLA DR-)

- Weakly differentiated memory CD4 (CD45RO+ / CD57-)

- TCM et TTM subsets (CD45RA- CCR7+/- CD27+)

Simian

Human


Therapy Meeting


� When? at PHI or during Chronic infection ?

� How ? combined strategies will be required to reduce HIV reservoirs

Residual

Replication

Immune

Activation

HIV Reservoirs

Latency

HIV Reservoirs

Latency

C Katlama, IAS-2011 Satellite meeting: New Concepts in HIV Immunepathogenesis, Treatment and Vaccines

Multiple factors ensuring HIV persistence

What is going to work?????

Targeting PHI for strategies of an HIV Cure?

• The sequence of events happening during PHI is a strong predictor

of the subsequent progression of the infection

• HIV-DNA decay for 1 year after cessation of therapy < 6 months

after seroconversion

• Control of viral rebound after therapy interruption < 3 weeks from

infection

� Preventing the early viral cytopathogenic effets on the CD4 compartment

� Reducing the size of viral reservoirs

� Reaching a host-virus equilibrium as a « functional cure » ??

(Goujard 2006)

(Strain 2005)

(Paci 2011)


Therapy Meeting


Patients

• Comparison of early-treated groups:

– Post Treatment Controllers : (PTC) n=11, HAART within 10 weeks of PHI, median 3 years on HAART, median 6 years after HAART interruption

– Early HAART : n=10, HAART within 10 weeks of PHI, median of 6 years under HAART

• To untreated groups:

– Elite Controlers : (EC) n=8, untreated patients with CD4 count > 600 cells/mm3

and viral load < 200 HIV-RNA copies/ml for at least 8 years

– Viremic patients : (V) n=10, untreated patients with CD4 count > 600 cells/mm3

and viral load > 200 HIV-RNA copies/ml for at least 8 years

Very early dissemination of the HIV reservoirs

Day 30 post-infection

C Bacchus and A Cheret et al. the ANRS Optiprim study

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

0

1

2

3

4

5

6

N

***

CM TM EM 4NA 4A CD8 Mono

*** *** *** *** ***

Lo

g c

op

ies

AD

N H

IV /

Mo

de

cellu

les


Therapy Meeting


Very early dissemination of the HIV reservoirs

Effect of early treatment:

the Post-Treatment Controllers (VISCONTI study)

Day 30 post-infection


OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

0

1

2

3

4

5

6

N

***


*** *** *** *** ***

Log

copi

es A

DN

HIV

/ M

o de

cel

lule

s

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

OPTVIS

0

1

2

3

4

5

6

N

***


*** *** *** *** ***

Log

copi

es A

DN

HIV

/ M

o de

cel

lule

s Post-Treatment

Controllers: (PTC)

pVL<500cp/ml

for a median 3.5 y

after 3-5 y ARV

initiated very early

at PHI (Hoqueloux et al. AIDS 2010)

Similar Distribution of the HIV reservoirin Elite Controlers (EC) and Post-Treatment Controlers (PTC):

Empty Symbols :

50% detection

threshold value C Bacchus and A Cheret et al. the ANRS Optiprim study; B Descours & V Avettand et al. Clin. Inf. Dis 2012

Low infection levels in long-lived Naive and centr al Memory CD4 T cells


Therapy Meeting


Conclusion 1

• A low HIV reservoir in PTC and Early HAART vs V patients

• PTC have the same HIV reservoir size and distribution as Elite

Controllers

• PTC Long-lived Naive CD4 T cells are poorly infecte d

• Viral replication recovered upon in vitro stimulation in all patients

and from all subsets

� When? at PHI or during Chronic infection ?

� How ? combined strategies will be required to reduce HIV reservoirs

Residual

Replication

Immune

Activation

HIV Reservoirs

Latency

HIV Reservoirs

Latency

C Katlama, IAS-2011 Satellite meeting: New Concepts in HIV Immunepathogenesis, Treatment and Vaccines

Multiple factors ensuring HIV persistence

What is going to work?????


Therapy Meeting


Contrary cases but from CCR5+ donors: C Rouzioux AIDS, 2007, Y. Levy, unpublished….

G Hutter et al.

Towards the Dream

of HIV eradication

How ?

Autran et al Science 2000, 200404, Nat Rev Immunol 2003,

Murphy Science 2009, IAS Working group Nat.Rev.Immunol. 2012

Hyper-ART +

Immune

interventions

HIV

RN

AH

IV D

NA

OptimizedcART

(control)

cART

Intensification

+ ImmuneIntervention

Anti_HIV

VRC

Vaccin

es

IL-7

Science May 2011

Is exhaustion of HIV Reservoirs feasible in Chronic infection?

The Eramune Projects

Rationale : TOC studies combining in CHI

� ARV super-intensification +

� immune interventions targeting :

- Eramune-01 => « latently » infected cells:

- IL-7 (results : November 2012)

- Eramune-02 => residual HIV replication:

- VRC vaccine (HIV DNA+ recAd5)

(results: 2013)


Therapy Meeting


Eradication: Role of IL-7 in inducing viral replication?

CD4 T Cell

Pi3K

JAK-1

AKTJAK-3

STAT-5

Survival,Proliferation

p27

CDC25A

TCRIL-7

HIV induction

IL-7 signaling evaluation

• IL-7R expression :

• Signal transduction via pSTAT5:

N CM TM EM

CD127 ExpressionRepresentative

patient

Median MFI

Median % 913507

79,53710

76,13676

75,93450

• IL-7 receptor :

• expressed on all CD4 T cell subsets

• though mainly in Naive CD4 T cells

• Transduce the IL-7 signal

• in all resting CD4 cell subsets



Therapy Meeting


IL-7 : Viral inductibility & Proliferation

EM

NCMTM

copi

es A

RN

VIH

/ A

DN

VIH

J0

IL-7 1 ng/ml

J3 J6 J8J10J1

3 J3 J6 J8J10J1

3 J3 J6 J8J10J1

3 J3 J6 J8J10J1

30123456789

Viral Inducibility Cell Proliferation Cell Survival

� IL-7

� capable to induce virus production:

� mainly in long-lived Naive CD4 T cells

� as in all Memory CD4 T cells,

� independently of cell proliferation


Purging the HIV reservoirs

Require synergistic effects of:

Anti-latency agents

Inducing CTLs or Abs

Therapeutic vaccines ?


Therapy Meeting


Dynamics of CTL and HIV-infected CD4 cells

HAART:

Quiescent Latently infected CD4

+ rare residual replicating cells

Provirus

CTL cannot detect latently infected cellsand proceed toward

clonal TEM/E contraction

CTLCTLCTLCTLCTLCTLCTLCTL

CTLCTL CTLCTLTCMTCM

HAART interruption or

Antigenic burst or anti-Latency agents

CTL are activated by CD4 T cells replicating HIV

CD4 Acutely replicate HIV

CTLCTL

CTLCTL

CTLCTL

CTLCTL

CTLCTL

Can a Therapeutic vaccine synergize

with an anti-latency agent?

Anti-latency agent (SAHA)

• Reactivates HIV production

• But not HIV-specific CTLs

HIV antigen stimulation:

• Reactivates HIV-specific CTL killing

⇒ Rationale for

a Therapeutic vaccine


Therapy Meeting


HLA-B27/57 restricted CD8 cell anti-HIV-Gag

Differentiation

Ga

g-s

pe

cifi

c C

D2

7+

TC

M C

D8

+ T

ce

lls

B57+ donors

Functional avidity

/Gag epitopes

Martinez V et al. J.I.D. 2005; Almeida et al. J Exp Med 2007, Blood 2009

X Jie et al. AIDS 2010

Magnitude

Ga

g-s

pe

cifi

c C

D8

+ T

ce

lls

B27 donors

HIV Reservoirs and

HLA B27/57

Descours &Avettand-Fenoel et al. CID 2012

Impact of HIV-specific CD8 T cells on the HIV Reser voirs :

Distinct impacts of HLA-B27- or B-57 on Gag-specific CD8 T cells on the

magnitude of the cell-associated HIV-DNA in the ALT ANRS CO-15 cohort:

�Reminiscent from the preservation of TCM numbers

in vaccinated macaques(Letvin et al. 2005)

� Strong Gag-specific CD8 T cells

negatively correlated with

HIV reservoirs in CD4 TCM cells

Distinct Hierarchy of HIV reservoirs in CD4 T cellsIn LTNPs : B Descours, V Avettand et al. CID 2011

� LTNP HIV Reservoirs

in quiescent CD4 subsets:

(TTM > TCM) ≥ (TEM > TN)

TN

TC

M

TTM

TE

M

101

102

103

104

0.0313

cell

HIV

-DN

A (co

pies

/mill

ions

cel

ls)

TN

TC

M

TTM

TE

M

0.00780.0078

0.0469

0.0078

HLA-B27/B57 non HLA-B27/B57

p=0.0081

HLA-B27/57+ Non HLA-B27/57

� TCM limited infection in HLA-B27+/57+

but not in aviremic HLA-B27/57- LTNPs


Therapy Meeting


B Descours et al CID 2012.

Anti-HIV CD8 T Lymphocytes :Key for the control of HIV Reservoirs inTCM

� Critical protection of long-lived

Central- Memory CD4

T Lymphocytes (TCM):

� required for maintaining

T cell Numbers and Function

in the long term

� preserved in LTNP / Controllers

HIV Transcriptionally active

HIV Transcriptionally inactive

Anti gag CD8 T cells

TN TTM TEMAntigens Antigens Antigens

HLA-B27/57 neg

TCM

HLA-B27/57pos

TN TCM TTM TEM

Naive

CD4+cell

CD45RA

CC

R7

Apoptosis

Turnover


CD4 T cells

CD45RA

CC

R7

memorymemoryCentral

Memory

CD4 T cells

CD45RA

CC

R7

CD45RA

CC

R7

memorymemoryEffector

Memory

CD4 T cells

CD27

CC

R7 memory

memoryTransitionnal

CD4 T cells

� A Therapeutic Vaccine should induce

� anti-HIV CD8 T cells or Abs

� to kill the residual replicating cells

� or block cell to cell HIV spreading

D Richmann et al. Science 2009

Purging

the

HIV

reservoirs ?

Anti-latency

CTLs/Abs

2008 -…: Emergence of a new therapeutic concept :

Can therapeutic vaccines help at purging the

HIV Reservoirs?

Autran et al NRI 2003, Science 2004, Murphy et al. Science 2009; D Richman Nat.Med. 2009; the IAS Working Scientific group on HIV Cure, NRI 2012

Lessons from past

Therapeutic vaccines against HIV ?

- Limited capacity

to control plasma virus bursts

- Manon-02 trial:

Facilitation of virus production

reflecting CD4 T cell activation

without CD8 T cells or Abs

BUT: No modification of the

cell-associated HIV-DNA

⇒ suggesting a lower plasticity

of the HIV reservoirs(B Autran et al. AIDS 2008)


Therapy Meeting


19 young adults (23 y.o)

on ART, HIV RNA < 50 cp/mL

vaccine: HIV env, gag, tat, rev, nef, RT

recombinant MVA +FowlPoxV

- 2 MVA: D0, W4

- 1 FPV: W8

Can a Therapeutic vaccine against HIV

decrease the HIV reservoirs ?

� Transient decrease in decay of latently infected CD4+ T cells

� Raises the question of the HIV reservoir read-out:

- Total cell-associated HIV-DNA: easy and standardizable

- Replication competent cells? Heavy, difficult to standardize…..

ERAMUNE-01 (Europe, PI: C Katlama)

SCREENING

ARM A (n=14) ARM B (n=14)

3 ARV

+ Intensification (raltegravir + maraviroc) +

IL-7(3: W8, 9,10)

Primary Evaluation

W -4

D0

Randomization

W8

W56

3 ARV + Intensification (raltegravir + maraviroc)

ERAMUNE-02 (USA, PI: R Murphy)

SCREENING

Primary Evaluation

ARM A (n=14)

3 ARV

+ Intensification

(raltegravir + maraviroc)

W -4

D0

Randomization

W8

W56

ARM B (n=14)

3 ARV + Intensification

(raltegravir + maraviroc)

+ VRC Vaccine: 3x HIVDNA016-00-VP

(W8,12, 16)

1x rAd5 (W32)VRC-HIVADV014-00-VP

The EraMune-01 and -02 Trials : Parallel Study Design

International, multicenter, randomized, non-comparative controlled study of therapeutic

intensification plus immunomodulation in HIV-infected patients with long-term viral suppression

� Similar Primary objective: Decrease in the HIV-1 viral reservoir� Results expected: Eramune-01: December 2012; Eramune-02: March 2013

VRC: HIVDNA016-00-VP : 3 DNA clade B HIV-1 Gag, Pol, or Nef

3 DNA HIV-1 Env clade A, B and C,

HIV-Ad5 VRC-HIVADV014-00-VP (clade B HIV-1 Gag Pol fusion protein,

+ clade A, B, and C Env proteins.

r-hIL-7 (CYT107) injections at 20 μg/Kg/week

(1 per week)


Therapy Meeting


Gene therapy

Maraviroc

Anti-inflammatory drugs- Statins

- OH-Chlorochin

Potential strategies to reduce HIV reservoirs

Residual

Replication

Immune

Activation

HIV Reservoirs

Latency

HIV Reservoirs

Latency

Massive CD4 T-cell depletion

Bacterial translocationARV Intervention

- Intensification

- NevirapineSystemic Inflammation

Viral Co-

Infections

Pre-Probiotics

Antiviral drugs

Anti-co-stimulatory molecules- anti PD1 / anti PDL1

- anti-CTLA4

- anti-CD137

CD4DC

Quiescent T cells activation- IL7

Pre/post-transcriptional

factors disruption- HDACi

- HMBA

Immune Intervention

- Anti-HIV vaccine

- IL7

Cellular Immunity

CD8

CD4

« Towards an HIV CURE »

Connecting researchers together

WHAT ELSE?WHAT ELSE?WHAT ELSE?WHAT ELSE?

A global scientific strategy defining research priorities

INTERNATIONAL ADVISORY BOARD

INTERNATIONAL SCIENTIFIC WORKING GROUP

Clinical Trials Basic Science

INTERNATIONAL CONSULTATIONS

Development Implementation

Launch

Workshop on towards a cure

F Barré-Sinoussi


Therapy Meeting


Univ Pierre et Marie Curie , Pitié-Salpétrière,

IFR Immunité-Cancer-Infection

CRIV (Centre de Recherches Intégrées sur le VIH)

Immunology, INSERM U945

Immunity to viruses immunogenetics HIV immunosenescence A Samri B Descours I Theodorou V Appay

A Guihot V Martinez J Guergnon J AlmeidaG Carcelain C Bacchus

ALT ANRS CO15 Cohort, VISCONTI, OPTIPRIM and Reservoir study groups:

Virology and serology : C Rouzioux, V Avettand , Univ. Paris-5

Viro-Immunology: A Saez-Cirion, Inst. Pasteur

Clinics: JP Clauvel, Saint-Louis Hosp. Univ Paris-7 ; D Sicard, Cochin Hosp. Univ. Paris-5

L Hoqueloux, CH Orléans; A Cheret CHU Lille-Tourcoing, France GISHEAL

ORVACS(Objectif recherche Vaccins SIDA)

An International ResearchPlatform

The Eramune trials

NIH VRC:

G Nabel

R Koup

J Cassazza

Cytheris : IL-7

Merck: Raltegravir

Pfizer: Maraviroc

RFH Group

M Youle,

S Kinloch et al.

AM Geretti

Professor Brigitte Autran - Mediscript - Medical Publishers · D N H I V / M o d e c e l l u l e s....

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