Main questions on HIV persistence and on obstacles to HIV eradication

1. Toward an HIV cure: Insight into residual viral replication, establishment of HIV reservoirs and understanding mechanism of persistence Main questions on HIV persistence and on obstacles to HIV eradication Jean-Pierre Routy M.D. McGill University Montreal

2. IAS international working group:

4. Even best candidates are not cured by HAART: “The Toronto patient” • Early infection treatment, plasma VL < 50 copies, x 10,5 years • HIV DNA undetectable from blood and sigmoid tissues at the time of the analysis • HAART discontinuation Chun, Kovacs, Fauci AIDS 2010; 24:2803

5. The Berlin patient: Treated for acute myeloid leukemia by allo-stem cell transplatation

6. “The Berlin patient”

7. ABC news December 17, 2010“A risky and inconvenient method” ABC News December 17, 2010

8. What does cure mean ? • Sterilizing cure: • No genetic material can be found in the host, HIV infection is eradicated • “Pax romana” or functional cure: • Some HIV genetic material remains in the host, but the immune system fully controls viral replication in absence HAART

9. Why HAART does not cure HIV ? • HAART only blocks HIV replication/entry • HAART does not kill infected cells: • The immune system should eliminate infected cells like • Persistence in long-lived cells • Integrated into the host cell nucleus • HIV DNA survives as long as the cell • 9% of our human genome is also made from old integrated retroviruses

10. What do we know on HIV-infected cells under HAART ? • Hematopoietic cells +/- • Macrophages + • Microglia + • Memory CD4 T cells +++

11. Heterogeneity of the infected memory CD4 T cells Central memory Transitional memory Naive Chomont et al Nat med 2009

12. Why residual viremia persists with HAART (few copies only) ? • Ongoing low viral replication: • Not allowing drug resistance development • New cells been infected • Reservoir maintained by replenishment • Localization: • Lymphoid tissues • Anatomic sanctuaries: CNS • Lower antiretroviral drug penetration • More antiretroviral drugs should do better

13. Residual plasma viremia and size of pro viral DNA in treated patients Reservoir size Viral load < 50 No correlation between CD4 and CD8 CD38 ceils and reservoir size Chun, Kovac, Fauci et al JID 2011; 204:135

14. Why residual viremia persists with HAART (few copies only) ? • Viral production by infected cells not undergoing lytic cell death • Decay kinetic with a flat phase 3 • Long lived cells • Virus released when cells divide • Central memory CD4 T cells: TCR dependant • Transitional memory CD4 T cells: Homeostatic • T cell proliferation associated with T cell activation Mathusalem: 969 years old

15. Role of T cell activation in the establishment and maintenance of reservoir Proliferation Activation Chomont et al Nat Med 2009 Da Fonseca et al IAS MOPE082

16. Factors associated with CD4 T cellactivation may impact reservoir size LDL LDL Corbeau P, J Reynes, Blood 2011; 117:5582 adapted

17. What are the relative contribution of mechanisms associated with HIV persistence on HAART ?

18. Obstacle to HIV eradication

19. Timing of HAART initiation and the reservoir size and localization • Limiting the pool of latently infected cells • Preserving immune functions • Reducing gut associated lymphoid tissue damage and in turn limiting subsequent inflammation triggered by systemic leakage of microbial products • Can this strategy be implemented on a large scale ?

20. CD4/CD8 ratio and duration of viremia drive the reservoir size Chomontet al. Nat Med June 2009

21. HAART intensification • Can HAART intensification completely suppress residual viral replication ? • Is there a threshold for a functionally important decay of the latent reservoir following intensified HAART ? • How long should we intensified treatment before assessing reservoir changes

22. Long-lived CD4 T cells:The Trojan Horse issue • Mechanisms involved in the generation and maintenance of memory CD4 T cells are also responsible for the establishment and persistence of HIV in the long-lived cellular compartment “Do not trust the Horse, Trojans Whatever it is, I fear the Greeks even bearing gifts” Laocoonte, Vatican Museum

23. Tools to monitors reservoir changes • Type of tests: • Ultra sensitive plasma viral load (RNA) • HIV DNA: integration • 2-LTR: replication • Integrated DNA infectious units • Cell associated RNA • Validation • Frequency of sampling

24. Tissue sampling for monitoring of HIV persistence • Blood: • Leukapheresis • Lymph nodes • Gut: • Rectum, colon, ileum • Central nervous system: • CSF • Genital fluids

25. Ethical and clinical trial issues • Toxicity of experimental therapy(ies) • Drug-drug interaction • Reservoir assessment: • Tissue markers • HAART discontinuation as a read out for study outcome • Quality of the informed consent • Study design

26. “Higher risk, higher hope”

27. Conclusion • Key topic at the Rome IAS conference • Translational research challenge • Community participation • International collaboration

28. Université de Montréal: Patricia Montéro Annie Gosselin Petronela Ancuta Cécile Tremblay Rejean Thomas Benoit Trottier Jean–Guy Baril Harold Dion VGTI Florida Rafick Sékaly Nicolas Chomont Cytheris: IL-7 Michel Morre Thérèse Croughs Université McGill: Rachid Boulassel Bertrand Lebouché Roger LeBlanc Richard Lalonde Marina Klein Martin Potter Alexanda de Pokomandi Norbert Gilmore Mark Wainberg CIHR/CTN: Joel Singer Jacquie Sas Jo Pankovich David Cox Acknowledgement

30. T cell survival and homeostatic proliferation Chomont, Sekaly et al Curr opin in HIV AIDS 2011;6: 30

31. Model for persistent infection in hematopoietic progenitor cells Mcnamara et al Curr Opin HIV AIDS 2010; 6:43

32. Diversité des formes du réservoir viral: Cellules latentes et productives

33. Cohen J Science; 2011; 332:784