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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 [email protected] 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 200 B Autran EACS 09 Infections Opportunistes ARV Réponses Immunes Cellules CD4/mm3 Charge VIH SIDA 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 ???? All serious non-AIDS Non-AIDS malignancy Renal CVD Liver Other non-AIDS death 0.2 B Hirschel et al. 2006….. 0.5 1.0 1.5 Adjusted hazard ratio < 400 vs. > 400 copies/mL 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 requires immune activation to replicate in activated CD4 T cells Antigens => HIV replicates and In lymphoïd tissues Cytokines where Activation takes place BAutran/03 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 Infection, Immune Activation and CD4 cell depletion CD4 Deficiency negatively correlates to Immune activation CD4 counts HIV load Immune Activation Immune responses despite induction of powerful immune responses against HIV 200 Where is Immune activation coming from ? B Autran EACS 09 T-cell activation and CD4 count Hunt, JID 2008 N= 30 HIV+ with VL < 75c/mL HIV-related apoptosis of the gut mucosal epithelia induces Microbial translocation Thus eliciting systemic immune activation JM. Brenchley, ….AT. Haase,and DC. Douek Systemic LPS from translocated Bacteria correlates with disease progression BAutran/06 Nat Med 2006 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 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? Through Inflammation and activation of macrophages B Autran EACS 09 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 20 CD8 activés DR+ 15 % positive cells 4 HIV 3 10 2 5 1 0 0 2 B Autran 2009 4 6 Mois 8 10 12 14 CD8 CD4 mémoires activés DR+ Infective cells(log10)/107PBMC CD4 activés DR+ Immune benefits of 10 years of fully suppressive HAART : Can CD4 cell recovery continue after 5 years of ART The Decamune study CD4 recovery LTU: Long Term Undetectability (10 years without Blips at any time: 800 N= 22 out of 800 pts treated for 10yrs) with median nadir CD4: 212/mm3 between 5 and 10 years with a 3rd positive CD4 cell slope CD4 / mm3 Sustained CD4 T cell recovery 600 400 200 Decamune 0 0 1 2 3 4 5 6 7 8 9 10 Years of ART => Normalisation of CD4 T cell activation (Guihot AIDS 2010) Normal levels of Activated CD4 T cells (9% Persisting low levels of CD8 activation Immune benefits of long term fully suppressive HAART : Is Immune Activation completely controlled ? Immune benefits of long term fully suppressive HAART : Control of Immune Activation is associated with better immune status prior to treatment : TREAT EARLY => BETTER LONG TERM CONTROL OF IMMUNE 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 G Hutter et al. The Dream of HIV eradication Contrary cases but from CCR5+ donors: C Rouzioux AIDS, 2007, Y. Levy, unpublished…. HIV RESERVOIRS at various stages of the HIV infection Effect of early and long term ART Data from the french ANRS Cohorts The Decamune Study (Guihot AIDS 2010) : Viral Reservoirs after 10 years ART DNA- copies /106 PBMC p = 0,05* p <0,0001* 3,000 1,000 600 400 200 0 DNA cp/MPBMC (log) LTU 157 2.2 STU 353 2.5 HIC 30 1.5 Similar results: Chun JID 2011 TREAT VERY EARLY : BEST CONTROL OF THE HIV RESERVOIRS Critical role of the Long lived CD4 T cells : Central memory T cells (TCM): required for long term maintenance of the immune functions A clue for a Therapeutic control of the HIV Reservoirs? Life span Naive CD4 TCM 10 Years (?) (> 3-6 mths) ? (1-3 mths?) TEM Effector (8-15 days) Apoptosis effector effector Effector CD4 T cells CCR7 memory Effector memory Memory CD4 T cells CCR7 Naive CD4+cell Transitional CD45RA Distribution of the HIV Reservoirs in CD4 cells during ARV CD45RA Central memory memory Memory CD4 T cells CCR7 CD45RA memory memory Transitionnal CD4 T cells CCR7 CCR7 N Chomont et al. Nature Medicine 2009 Turnover CD27 CD45RA Proviral HIV DNA Predominates in Memory CD4 T cells with 6months ½ life Quasi-undetectable in Naive Ly with 10 y lifespan 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 ? Eramune: Study design cART Intensification Optimized cART (control) IL-7 + Immune Intervention Anti_HIV Vaccines HIV DNA HIV RNA Hyper-ART + Immune interventions 2 parallel International Clinical Trials currently ongoing: Eramune-01 & -02 Autran et al Science 2000, 2004, Nat Rev Immunol 2003, Murphy Science 2009 Why hav’nt we an HIV vaccine yet? • A failure but not a lack of researches • Obstacles against HIV vaccines : HIV escape – Immediate and definitive HIV Integration in host genome = Trojan Horse – HIV Variability in Antibody and T cell epitopes (Enveloppe, Tat, Nef, Gag) – Weak neutralizing antibodies Difficulties illustrated by the lack of spontaneous recovery from the infection BA ADVAC10 Obstacles to HIV Vaccines: Kinetics of early infection and HIV prevention A Haase, Nature Reviews Immunology 2010 : Targets for vaccinal responses to HIV from Targets for vaccinal responses to HIV from Targets for vaccinal responses to HIV from