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