New concepts in HIV Immunology

Pr Brigitte AUTRANLab. Immunité et Infections, INSERM U945

Institut Fédératif de Recherches Immunité-Cancer-InfectionHôpital Pitié-Salpétrière

Université Pierre et Marie Curie, Parisbrigitte.autran@psl.aphp.fr

B Autran EACS 10

1981 - 1997 - 2007 : AIDS and Immune Deficiencies :

• The (only?) Complication of the HIV infection, • occurring despite strong immune responses to HIV

• Immune Reconstitution with ARV

B Autran EACS 09

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SIDAInfections

Opportunistes

ARV

1997 – 2006: Limitations of ARV : Partial restoration of Immunity to HIV

=> Concepts : « auto-vaccination »

by treatment interruption (STI)

Primo-infectionJ Lisziewicz et al. ….E. Rosenberg et al.,

1989, 2000

CTL CD4 help virus

Infection Chronique: G Ortiz et al., G. Carcelain et al. B Hirschel et al. …..

1989 ….2002

1998 – 2007 : The « Burial » of the STI concept : Lack of viral control after repeated STI

despite rebounds in immune responses SMART: Increased Frequency of complications

HIV-related: opportunistic Infections Cardiovascular: HIV-related ????

Renal

Liver

All serious non-AIDS

CVD

Non-AIDS malignancy

Other non-AIDS death

Adjusted hazard ratio < 400 vs. > 400 copies/mL

1.0 1.50.50.2

B Hirschel et al. 2006….. El Sadr et al. 2007

New questions & Novel conceptsin the Immunology of the HIV infection

• Immune activation and Immunopathology of the HIV infection

• Immune Benefits of Long term antiretroviral therapy ?

• Immune control of HIV and the dream of HIV eradication …

B Autran EACS 09

Current issues in HIV immunolgy

• Immune activation and Immunopathology of the HIV infection:

the vicious circle

– What’s new ?

– Current issues:

• Sources of immune activation?

• Consequences of immune activation and cardiovascular alterations

• Markers of immune activation

• Benefits of ART?

• Immune Benefits of Long term antiretroviral therapy

• Immune control of HIV and the dream of HIV eradication ……

B Autran EACS 09

HIV Infection, Immune Activation and CD4 cell depletion

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CD4 Deficiency negatively correlates to Immune activation

despite induction of powerful immune responses against HIV

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Where is Immune activation coming from ?

T-cell activation and CD4 count

Hunt, JID 2008 N= 30 HIV+ with VL < 75c/mL

Antigens

and

Cytokines

=> HIV replicates

In lymphoïd tissues

where

Activation takes place

BAutran/03

HIV requires immune activation toreplicate in activated CD4 T cells

Is this new?No! In 1983 F Barré-Sinoussi et al. discovered

LAV/HIV in a lymph node 1 year before all other groups that looked for HIV in the blood

Science, May 1983, 220, 368

HIV-related apoptosis of the gut mucosal epithelia induces Microbial translocation

Thus eliciting systemic immune activation JM. Brenchley, ….AT. Haase,and DC. Douek Nat Med 2006

BAutran/06

Systemic LPS from translocated

Bacteria correlates with disease progression

Systemic LPS binds Monocytic receptors (CD14)

and elicitsrelease of pro-inflammatory cytokines

What’s new? Chronic Inflammation/activation plays a key role in immunopathology of HIV

tat,

Appay V et al, J Pathol 08

Inflammation/activation chronique et immunopathologie du VIH

from Appay V et al, J Pathol 08

Secretion of Pro-inflammatory

Cytokines

IL-1, IL-6, TNF-a,….

Chimiokines

MCP-1, CX3CL1, RANTES,….

Inflammation-related DisordersAtherosclerosis

Osteoporosis

Neurocognitive

Degeneration

= inflamm-ageing ?

How can HIV induce atherosclerosis?Through Inflammation and activation of

macrophages

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et al.

Univariate & multivariate models assessing the association between cardiovascular

markers and HIV RNA at Wk 12 of ART interruption

A Calmy et al & the STACCATO Study Group

Inflammation/activation chronique et immunopathologie du VIH

from Appay V et al, J Pathol 08

Secretion of Pro-inflammatory

Cytokines

IL-1, IL-6, TNF-a,….

Chimiokines

MCP-1, CX3CL1, RANTES,….

Inflammation-related DisordersAtherosclerosis

Osteoporosis

Neurocognitive

Degeneration

= inflamm-ageing ?

Current issues in HIV immunolgy• Immune activation and Immunopathology of the HIV infection: the vicious

circle

• Immune Benefits of Long term antiretroviral therapy

– Early effects of ART on Immune activation

– Long Term benefits of ART?

• Can Immune reconstitution continue 10 years after onset of ART?

• Can Long Term ART restore immune defenses?

• Can Long Term ART exhausts the reservoirs of HIV?

• Immune control of HIV and the dream of HIV eradication

B Autran EACS 09

1997: Immune Restoration and Regression of hyperactivation with ART

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CD4 activés DR+

CD4 mémoiresactivés DR+

CD8 activés DR+

HIV

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Decreased proportions of activated CD4 and CD8 T cells

CD

8

Decreased CD38 expression per CD6 T cells

B Autran 2009

LTU: Long Term Undetectability

(10 years without Blips at any time:

N= 22 out of 800 pts treated for 10yrs)

with median nadir CD4: 212/mm3

Sustained CD4 T cell recovery

between 5 and 10 years

with a 3rd positive

CD4 cell slope

=> Normalisation of CD4 T cell

activation

(Guihot AIDS 2010)

Immune benefits of 10 years of fully suppressive HAART :

Can CD4 cell recovery continue after 5 years of ART

The Decamune study

Years of ART

CD

4 /

mm

3

0

200

400

600

800

1 2 3 4 5 6 7 8 9 100

Decamune

CD4 recovery

Normal levels of Activated CD4 T cells (9%)

Persisting low levels of CD8 activation

Current issues in HIV immunology

• Immune activation and Immunopathology of the HIV

infection: the vicious circle

• Immune Benefits of Long term antiretroviral therapy

• Immune Control of the HIV Reservoirs and the dream of

HIV eradication?...

B Autran EACS 09

Dynamics of the latent reservoir in viraemic and aviraemic patients(Siliciano et al. 2007)

No residual replication= No « internal « re-seeding of the HIV reservoirs ???

Estimated lifespan of the HIV reservoirs:- 64 years (Finzi et al.)

- 69 years (Chomont et al.)

Maintenance of a long term HIV reservoir in HAART suppressed patients

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

G Hutter et al.

The Dream

of HIV eradication

Reduction of the HIV Reservoirs with a continuous

fully-suppressive ARV?

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The Decamune Study (Guihot AIDS 2010) :

Low Viral Reservoirs after 10 years HIV suppression

With ART and continuous CD4 recovery

Distribution of the HIV Reservoirs in CD4 cells

during ARV N Chomont et al. Nature Medicine 2009

Proviral HIV DNA Predominates in

Central Memory CD4 T cells with 6months ½ life

Quasi-undetectable in Naive ly with 10 y lifespan

Emergence of new therapeutic concepts :

From treatment interruption to treatment intensification:

Towards a Functional Cure ?

• To test whether an « add-on »

strategy including :

• ARV super-intensification plus

• Immune-Based Therapies targeting:

• Cells actively replicating HIV

• Cells latently infected

• Can promote decay or exhaustion of

• residual plasma VL

• HIV reservoirs

HIV

RN

AH

IV D

NA

ARV

Super ARV-intensification

Immune Based InterventionsRichman et al. Science 2009, R. Murphy, B. Autran, C Katlama et al. Science 2009

Purging the HIV reservoirs?

IL-7

CTLs

Can the Immune system help

at controlling the Reservoirs?

Is exhaustion of HIV Immune Reservoirs feasible ? The Eramune Projects

Can the most potent combinations of ARV and immune interventions - That activates « latently » infected cells- That targets cells actively replicating HIV

Exhaust the HIV reservoirs ?

Autran et al Science 2000, 2004, Nat Rev Immunol 2003, Murphy Science 2009

Hyper-ART + Immune interventions

HIV

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OptimizedcART

(control)

OptimizedcART

(control)

cART Intensification

cART Intensification

+ ImmuneIntervention

+ ImmuneIntervention

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Eramune: Study design

IL-7

2 parallel International Clinical Trials currently ongoing: Eramune-01 & -02

Univ Pierre et Marie Curie Paris-6, CHU Pitié-Salpétrière,

Immunology, INSERM U945 Immunity to viruses immunogenetics HIV immunosenescence A Samri B Descours I Theodorou V Appay, X Jie V Martinez J Gueurgnon J AlmeidaA Schnuriger B M da SilvaW Lu*G Carcelain

Virology: Statistics : INSERM U720 C Dalban, D. CostagliolaH Agut Clinics: C Katlama, R Tubiana, MA Valantin….V CalvezAG Marcellin

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