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New concepts in HIV Immunology

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. SIDA Infections

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New concepts in HIV Immunology

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  1. 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

  2. SIDA Infections Opportunistes ARV Cellules CD4/mm3 Charge VIH Réponses Immunes 200 • 1981 - 1997 - 2007 : AIDS and Immune Deficiencies : • The (only?) Complication of the HIV infection, • occurringdespitestrong immune responses to HIV • Immune Reconstitution with ARV B Autran EACS 09

  3. Primo-infection J Lisziewicz et al. ….E. Rosenberg et al., 1989, 2000 Infection Chronique: G Ortiz et al., G. Carcelain et al. B Hirschel et al. ….. 1989 ….2002 CTL CD4 help virus 1997 – 2006: Limitations of ARV : • Partial restoration of Immunity to HIV • => Concepts : « auto-vaccination » • by treatment interruption (STI)

  4. All serious non-AIDS Non-AIDS malignancy Renal CVD Liver Other non-AIDS death 0.2 0.5 1.0 1.5 Adjusted hazard ratio < 400 vs. > 400 copies/mL 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 ???? B Hirschel et al. 2006….. El Sadr et al. 2007

  5. 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

  6. 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

  7. CD4 counts HIV load Immune responses Immune Activation 200 HIV Infection, Immune Activation and CD4 cell depletion • CD4 Deficiency negatively correlates to Immune activation • despite induction of powerful immune responses against HIV • Where is Immune activation coming from ? B Autran EACS 09

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

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

  10. 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

  11. 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

  12. tat, What’s new? Chronic Inflammation/activation plays a key role in immunopathology of HIV Appay V et al, J Pathol 08

  13. 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

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

  15. 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

  16. 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

  17. 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

  18. 20 CD4 activés DR+ CD4 mémoiresactivés DR+ 4 CD8 activés DR+ 15 CD8 HIV 3 % positive cells 10 Infective cells(log10)/107PBMC 2 5 1 0 0 2 4 6 8 10 12 14 Mois 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 B Autran 2009

  19. CD4 recovery 800 600 CD4 / mm3 400 200 Decamune 0 0 1 2 3 4 5 6 7 8 9 10 Years of ART Immune benefits of 10 years of fully suppressive HAART :Can CD4 cell recovery continue after 5 years of ART The Decamune study • 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

  20. 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

  21. 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)

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

  23. 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 The Decamune Study (Guihot AIDS 2010) : p = 0,05* p <0,0001* 3,000 1,000 600 DNA- copies /106 PBMC 400 200 0 LTU STU HIC DNA cp/MPBMC 157 353 30 (log) 2.2 2.5 1.5 • Proviral HIV DNAPredominates in • Central Memory CD4 T cells with 6months ½ life • Quasi-undetectable in Naive ly with 10 y lifespan Low Viral Reservoirs after 10 years HIV suppression With ART and continuous CD4 recovery

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

  25. Can the Immune system help • atcontrolling the Reservoirs? IL-7 Purging the HIV reservoirs? CTLs

  26. Hyper-ART + Immune interventions HIV DNA HIV RNA 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 Optimized cART (control) cART Intensification + Immune Intervention Anti_HIV Vaccines 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

  27. 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

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