New concepts in HIV: HIV immunopathogenesis, treatment and vaccine strategies - report back
from pre-conference
Nicolas Chomont
VGTI-Florida
Christine Katlama: The HAART reality
HAART is not perfect!• Long term Toxicity• CD4/VL monitoring• Resistance• Cost
New objectives for HIV therapy• Increased survival, stop progression, stop transmission• Decrease drug burden (number of ARV) to decrease
toxicity and cost• Stop HAART (at least transitorily)• Functional cure / Eradication
How can we measure the efficacy of interventions aimed at reducing the viral reservoirs?
Doug Richman: Measuring HIV persistence
Sensitivity and precision of current assays?
S. Lewin and C. Rouzioux, AIDS 2011
Mechanisms of HIV persistence
Residual viremia in treated subjects:- Ongoing viral replication?- Viral production by long lived cells?
Viral replication
Viral productionHAART
Viral production: Identifying the source
Large variety of candidates:
- CD4 T cells- Macrophages (Mario Stevenson)- Hematopoietic stem cells (C. Carter and K. Collins)- CNS- Others
• We need to explore tissues (cell sorting and RNA/DNA quantification)
• Can we match the sequence of the virus in plasma with the sequence in other compartments?
• Intensification with drugs that penetrate tissues?
Doug Richman: Mechanisms of HIV persistence
Evidences for the absence of ongoing viral replication• Little or no impact of treatment intensification• No evolution (resistance to ARV)
BUT
• Buzon et al (Nat Med 2010) observed increased levels of 2-LTR circles upon Raltegravir intensification and reduced levels of activation
• Yukl et al (AIDS 2010) observed an impact of HAART intensification in the ileum (unspliced HIV RNA)
C. Katlama: Optimal suppression of viral replication
• Nevirapine is associated with a higher rate of VL<1 copy/mL when compared with EFV or LPV (Bonora, J Med Virol 2009)
• 40 virally suppressed patients with VL<1 copy/mL
Some of them still show high levels of immune activation (n=17) which are associated with:
• A low Nadir CD4• A low CD4/CD8 ratio (ongoing replication somewhere, bacterial
translocation?)
Is residual viremia a good marker to monitor HIV persistence?
The VISCONTI patients
Five out of 32 patients who received very early and prolonged antiretroviral therapy showed sustained immunovirological control for more than 6 years of treatment discontinuation.
2 conditions:• Treat early (median 2.3 weeks)• Treat for long (median 5 years)
CD4 TCM cell survival
Suberoylanilide hydroxamic acid
Histone deacetylase inhibitors
SAHA
Targeting the latent reservoir
D. Margolis, D. Hazuda, C. VanLint, A. Savarino
PD-1 expression correlates with the reservoir size
0 10 20 301
10
100
1000
10000
% PD-1+ T cells
Inte
gra
ted
HIV
DN
A c
op
ies
per
106
CD
4+ T
cel
ls
p=0,01
Targeting the cells: A role for PD-1 in HIV latency
CD3/CD28 + IgG2CD3/CD28 + PD-L1
NS
0 3 6 91
10
100
1000
10000
100000
1000000
p2
4 (
pg
/ml)
Time (d)
The negative signal conferred by the PD-1/PD-L1 interaction inhibits viral production in primary CD4+T cells from viremic donors
CD4 T cell homeostaticproliferation
IL-15
IL-7
IL-7: Necessary for homeostatic renewal
IL-15: Prompts cell maturation and viral replication
Targeting the proliferative reservoir
Correlates of control
• T cells predict control (but not protection, Gary Nabel)
• The magnitude and function of CD8 T cells are associated with control of the viral reservoir (Brigitte Autran).
• NK cells (and their KIR receptors) are associated with viral control (Marcus Altfeld)
Boosting immune responses: Vaccines
Interventions for HIV Cure
Reduce residual replication/production: Optimize HAART (J. Martinez Picado, Stefano Vella)• Intensification• Drug penetrationReduce immune activation (Steve Deeks)• Anti-inflammatory drugs• Reduce gut damage and /or microbial translocation• Anti CMV drugsTarget latent reservoirs• IL-7 (Eramune) or anti IL-7• HDAC• Anti PD-1• Gene Therapy (Jan Van Lunzen)Immune control of reservoirs (Brigitte Autran)• IL-7• HIV-specific IgG2 are associated with control in LTNP• NK cells
C U
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