New concepts in HIV Immunology Pr Brigitte AUTRAN Lab. Immunité et Infections, INSERM U945 Institut Fédératif de Recherches Immunité-Cancer-Infection Hôpital Pitié-Salpétrière Université Pierre et Marie Curie, Paris brigitte.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 Réponses Immunes Cellules CD4/mm3 Charge VIH 200 SIDA Infections Opportunistes ARV B Autran EACS 09

1997 – 2006: Limitations of ARV : Partial restoration of Immunity to HIV => Concepts : « auto-vaccination » by treatment interruption (STI) Primo-infection J 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 1.5 0.5 0.2 B Hirschel et al. 2006….. El Sadr et al. 2007

New questions & Novel concepts in 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 CD4 Deficiency negatively correlates to Immune activation despite induction of powerful immune responses against HIV Immune responses Immune Activation CD4 counts HIV load 200 Where is Immune activation coming from ? B Autran EACS 09

T-cell activation and CD4 count N= 30 HIV+ with VL < 75c/mL Hunt, JID 2008

HIV requires immune activation to Activation takes place replicate in activated CD4 T cells => HIV replicates In lymphoïd tissues where Activation takes place Antigens and Cytokines BAutran/03

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

Thus eliciting systemic immune activation 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 Systemic LPS from translocated Bacteria correlates with disease progression Systemic LPS binds Monocytic receptors (CD14) and elicitsrelease of pro-inflammatory cytokines BAutran/06

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 Secretion of Pro-inflammatory Cytokines IL-1b, IL-6, TNF-a,…. Chimiokines MCP-1, CX3CL1, RANTES,…. Inflammation-related Disorders Atherosclerosis Osteoporosis Neurocognitive Degeneration = inflamm-ageing ? from Appay V et al, J Pathol 08

How can HIV induce atherosclerosis How can HIV induce atherosclerosis? Through Inflammation and activation of macrophages B Autran EACS 09

markers and HIV RNA at Wk 12 of ART interruption A Calmy et al & the STACCATO Study Group et al. Univariate & multivariate models assessing the association between cardiovascular markers and HIV RNA at Wk 12 of ART interruption

Inflammation/activation chronique et immunopathologie du VIH Secretion of Pro-inflammatory Cytokines IL-1b, IL-6, TNF-a,…. Chimiokines MCP-1, CX3CL1, RANTES,…. Inflammation-related Disorders Atherosclerosis Osteoporosis Neurocognitive Degeneration = inflamm-ageing ? from Appay V et al, J Pathol 08

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 Decreased proportions of activated CD4 and CD8 T cells Decreased CD38 expression per CD6 T cells % positive cells Infective cells(log10)/107PBMC 5 10 15 20 2 4 6 8 12 14 1 3 CD4 activés DR+ CD4 mémoires activés DR+ CD8 activés DR+ HIV Mois CD8 B Autran 2009

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 CD4 / mm3 200 400 600 800 1 2 3 4 5 6 7 8 9 10 Decamune CD4 recovery 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) 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

Maintenance of a long term HIV reservoir in HAART suppressed patients Estimated lifespan of the HIV reservoirs: 64 years (Finzi et al.) 69 years (Chomont et al.) No residual replication = No « internal « re-seeding of the HIV reservoirs ??? Dynamics of the latent reservoir in viraemic and aviraemic patients (Siliciano et al. 2007)

The Dream of HIV eradication G Hutter et al. Contrary cases but from CCR5+ donors: C Rouzioux AIDS, 2007, Y. Levy, unpublished….

Reduction of the HIV Reservoirs with a continuous fully-suppressive ARV? 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 200 400 600 1,000 3,000 LTU STU HIC DNA- copies /106 PBMC cp/MPBMC 157 353 30 p = 0,05* p <0,0001* (log) 2.2 2.5 1.5 DNA The Decamune Study (Guihot AIDS 2010) : Low Viral Reservoirs after 10 years HIV suppression With ART and continuous CD4 recovery

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 RNA HIV DNA ARV Super ARV-intensification    Immune Based Interventions Richman et al. Science 2009, R. Murphy, B. Autran, C Katlama et al. Science 2009

Can the Immune system help at controlling the Reservoirs? IL-7 Purging the HIV reservoirs? CTLs

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 ? Hyper-ART + Immune interventions HIV RNA HIV DNA Optimized cART (control) Intensification + Immune Intervention Anti_HIV Vaccines Eramune: Study design IL-7 2 parallel International Clinical Trials currently ongoing: Eramune-01 & -02 Autran et al Science 2000, 2004, Nat Rev Immunol 2003, Murphy Science 2009

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 Almeida A Schnuriger B M da Silva W Lu* G Carcelain Virology: Statistics : INSERM U720 C Dalban, D. Costagliola H Agut Clinics: C Katlama, R Tubiana, MA Valantin…. V Calvez AG Marcellin The ORVACS Network