4 Christine Katlama: The HAART reality HAART is not perfect!• Long term Toxicity• CD4/VL monitoring• Resistance• CostNew objectives for HIV therapyIncreased survival, stop progression, stop transmissionDecrease drug burden (number of ARV) to decrease toxicity and costStop HAART (at least transitorily)Functional cure / EradicationHow can we measure the efficacy of interventions aimed at reducing the viral reservoirs?
5 Doug Richman: Measuring HIV persistence Sensitivity and precision of current assays?S. Lewin and C. Rouzioux, AIDS 2011
7 Mechanisms of HIV persistence Residual viremia in treated subjects:- Ongoing viral replication?- Viral production by long lived cells?Viral replicationHAARTViral production
8 Viral production: Identifying the source Large variety of candidates:CD4 T cellsMacrophages (Mario Stevenson)Hematopoietic stem cells (C. Carter and K. Collins)CNSOthersWe 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?
9 Doug Richman: Mechanisms of HIV persistence Evidences for the absence of ongoing viral replicationLittle or no impact of treatment intensificationNo evolution (resistance to ARV)BUTBuzon et al (Nat Med 2010) observed increased levels of 2-LTR circles upon Raltegravir intensification and reduced levels of activationYukl et al (AIDS 2010) observed an impact of HAART intensification in the ileum (unspliced HIV RNA)
10 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/mLSome of them still show high levels of immune activation (n=17) which are associated with:A low Nadir CD4A low CD4/CD8 ratio (ongoing replication somewhere, bacterial translocation?)Is residual viremia a good marker to monitor HIV persistence?
11 HIV DNA in PBMCs Acute Chronic LTNP controllers Visconti S. Lewin and C. Rouzioux, AIDS 2011
12 The VISCONTI patientsFive 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)
14 Rafick Sekaly: Mechanisms of HIV persistence Viral replicationT cell survivalProliferation
15 Targeting the latent reservoir Suberoylanilide hydroxamic acid SAHACD4 TCM cell survivalHistone deacetylase inhibitorsSuberoylanilide hydroxamic acidD. Margolis, D. Hazuda, C. VanLint, A. Savarino
16 Targeting the cells: A role for PD-1 in HIV latency p24 (pg/ml)Time (d)CD3/CD28 + IgG2CD3/CD28 + PD-L1NSThe negative signal conferred by the PD-1/PD-L1 interaction inhibits viral production in primary CD4+T cells from viremic donorsPD-1 expression correlates with the reservoir size
17 Targeting the proliferative reservoir IL-15CD4 T cellhomeostaticproliferationIL-7IL-7: Necessary for homeostatic renewalIL-15: Prompts cell maturation and viral replication
18 Boosting immune responses: Vaccines Correlates of controlT 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)
19 Interventions for HIV Cure Reduce residual replication/production: Optimize HAART (J. Martinez Picado, Stefano Vella)IntensificationDrug penetrationReduce immune activation (Steve Deeks)Anti-inflammatory drugsReduce gut damage and /or microbial translocationAnti CMV drugsTarget latent reservoirsIL-7 (Eramune) or anti IL-7HDACAnti PD-1Gene Therapy (Jan Van Lunzen)Immune control of reservoirs (Brigitte Autran)IL-7HIV-specific IgG2 are associated with control in LTNPNK cellsC U R E