Download Treatments to modulate HIV reservoirs

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
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 ?
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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
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
Why residual viremia persists with
HAART (few copies only) ?
• Viral production by infected cells not
undergoing lytic cell death
Mathusalem:
969 years old
– 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
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
Factors associated with CD4 T cell
activation may impact reservoir size
LDL
LDL
Corbeau P, J Reynes, Blood 2011; 117:5582 adapted
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
“Do not trust the Horse, Trojans
Whatever it is, I fear the Greeks even
bearing gifts”
Laocoonte, Vatican Museum
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
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Key topic at the Rome IAS conference
Translational research challenge
Community participation
International collaboration
Acknowledgement
• Université de Montréal:
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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:
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Rachid Boulassel
Bertrand Lebouché
Roger LeBlanc
Richard Lalonde
Marina Klein
Martin Potter
Alexanda de Pokomandi
Norbert Gilmore
Mark Wainberg
• CIHR/CTN:
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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