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. 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 Réponses Immunes Cellules CD4/mm3 Charge VIH 200 SIDA Infections Opportunistes ARV

3. 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 copies/mL 1.01.50.5 0.2 B Hirschel et al. 2006….. El Sadr et al. 2007

4. 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

5. Current issues in HIV immunolgy Immune activation and Immunopathology of the HIV infection: the vicious circle –Whats 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

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

7. 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

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

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

10. 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

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

12. 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 Disorders Atherosclerosis Osteoporosis Neurocognitive Degeneration = inflamm-ageing ?

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

14. 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

15. 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 Disorders Atherosclerosis Osteoporosis Neurocognitive Degeneration = inflamm-ageing ?

16. 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

17. 1997: Immune Restoration and Regression of hyperactivation with ART Decreased proportions of activated CD4 and CD8 T cells CD8 Decreased CD38 expression per CD6 T cells B Autran 2009

18. 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 CD4 / mm 3 0 200 400 600 800 123456789100 Decamune CD4 recovery Normal levels of Activated CD4 T cells (9%) Persisting low levels of CD8 activation

19. Immune benefits of long term fully suppressive HAART : Is Immune Activation completely controlled ?

20. 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

21. 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

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

23. HIV RESERVOIRS at various stages of the HIV infection Effect of early and long term ART Data from the french ANRS Cohorts TREAT VERY EARLY : BEST CONTROL OF THE HIV RESERVOIRS 0 200 400 600 1,000 3,000 LTUSTUHIC DNA- copies /10 6 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) : Viral Reservoirs after 10 years ART Similar results: Chun JID 2011

24. 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? Distribution of the HIV Reservoirs in CD4 cells during ARV N Chomont et al. Nature Medicine 2009 Proviral HIV DNA Predominates in Memory CD4 T cells with 6months ½ life Quasi-undetectable in Naive Ly with 10 y lifespan Naive CD4+cell CD45RA CCR7 Apoptosis Turnover effector Effector CD4 T cells CD45RA CCR7 memory Central Memory CD4 T cells CD45RA CCR7 CD45RA CCR7 memory Effector Memory CD4 T cells CD27 CCR7 memory Transitionnal CD4 T cells Life span Naive CD4 TCM Transitional TEMEffector 10 Years (?) (> 3-6 mths) ? (1-3 mths?) (8-15 days)

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

26. 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 RNA HIV DNA Optimized cART (control) cART Intensification + Immune Intervention Anti_HIV Vaccines Eramune: Study design IL-7 2 parallel International Clinical Trials currently ongoing: Eramune-01 & -02

27. Why havnt 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

28. Obstacles to HIV Vaccines: Kinetics of early infection and HIV prevention A Haase, Nature Reviews Immunology 2010 :

30. Targets for vaccinal responses to HIV from

31. Targets for vaccinal responses to HIV from

32. Targets for vaccinal responses to HIV from