main questions on hiv persistence and on obstacles to hiv eradication
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
Main questions on HIV persistence and
on obstacles to HIV eradication
Jean-Pierre Routy M.D.McGill University
Montreal
Toward an HIV cure: Insight into residual viral replication, establishment of HIV reservoirs and understanding
mechanism of persistence
IAS international working group:
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
The Berlin patient: Treated for acute myeloid leukemia by allo-stem cell transplatation
“The Berlin patient”
ABC news December 17, 2010“A risky and inconvenient method”
ABC News December 17, 2010
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
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
What do we know on HIV-infected cells under HAART ?
• Hematopoietic cells +/-• Macrophages +• Microglia +• Memory CD4 T cells +++
Heterogeneity of the infected memory CD4 T cells
Naive Central memory
Transitional memory
Chomont et al Nat med 2009
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
Residual plasma viremia and size of pro viral DNA in treated patients
Chun, Kovac, Fauci et al JID 2011; 204:135No correlation between CD4 and CD8 CD38 ceils and reservoir size
Reservoir size
Viral load < 50
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
Role of T cell activation in the establishment and maintenance of reservoir
Chomont et al Nat Med 2009Da Fonseca et al IAS MOPE082
Activation Proliferation
Factors associated with CD4 T cellactivation may impact reservoir size
Corbeau P, J Reynes, Blood 2011; 117:5582 adapted
LDL
LDL
What are the relative contribution of mechanisms associated with HIV persistence on HAART ?
Obstacle to HIV eradication
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 ?
CD4/CD8 ratio and duration of viremia drive the reservoir size
Chomont et al. Nat Med June 2009
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
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
Laocoonte, Vatican Museum
“Do not trust the Horse, Trojans Whatever it is, I fear the Greeks even bearing gifts”
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
Tissue sampling for monitoring of HIV persistence
• Blood:– Leukapheresis
• Lymph nodes• Gut:
– Rectum, colon, ileum• Central nervous system:
– CSF• Genital fluids
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
“Higher risk, higher hope”
Conclusion
• Key topic at the Rome IAS conference• Translational research challenge• Community participation• International collaboration
Acknowledgement• 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
T cell survival and homeostatic proliferation
Chomont, Sekaly et al Curr opin in HIV AIDS 2011;6: 30
Model for persistent infection in hematopoietic progenitor cells
Mcnamara et al Curr Opin HIV AIDS 2010; 6:43
Diversité des formes du réservoir viral: Cellules latentes et productives
Cohen J Science; 2011; 332:784