Presentation on theme: "New concepts in HIV: HIV immunopathogenesis, treatment and vaccine strategies - report back from pre-conference Nicolas Chomont VGTI-Florida."— Presentation transcript:
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
Optimal suppression of viral replication
Mechanisms of HIV persistence Residual viremia in treated subjects: - Ongoing viral replication? - Viral production by long lived cells? Viral replication Viral production HAART
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?
Acute Chronic LTNP controllers Visconti HIV DNA in PBMCs S. Lewin and C. Rouzioux, AIDS 2011
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)
Circulating virus HAART Circulating virus Time HAART
T cell survival Proliferation Viral replication Rafick Sekaly: Mechanisms of HIV persistence
CD4 T CM 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 p=0,01 Targeting the cells: A role for PD-1 in HIV latency CD3/CD28 + IgG2 CD3/CD28 + PD-L1 NS p24 (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 homeostatic proliferation 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 penetration Reduce immune activation (Steve Deeks) Anti-inflammatory drugs Reduce gut damage and /or microbial translocation Anti CMV drugs Target 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 R E