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 HAART Viral production

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?

HIV DNA in PBMCs Acute Chronic LTNP controllers Visconti 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)

HAART Circulating virus Circulating virus Time HAART

Rafick Sekaly: Mechanisms of HIV persistence Viral replication T cell survival Proliferation

Targeting the latent reservoir Suberoylanilide hydroxamic acid SAHA CD4 TCM cell survival Histone deacetylase inhibitors Suberoylanilide hydroxamic acid D. Margolis, D. Hazuda, C. VanLint, A. Savarino

Targeting the cells: A role for PD-1 in HIV latency p24 (pg/ml) Time (d) CD3/CD28 + IgG2 CD3/CD28 + PD-L1 NS The negative signal conferred by the PD-1/PD-L1 interaction inhibits viral production in primary CD4+T cells from viremic donors PD-1 expression correlates with the reservoir size

Targeting the proliferative reservoir IL-15 CD4 T cell homeostatic proliferation IL-7 IL-7: Necessary for homeostatic renewal IL-15: Prompts cell maturation and viral replication

Boosting immune responses: Vaccines 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)

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