Washington D.C., USA, July 2012www.aids2012.org Track A – BASIC SCIENCE Rapporteur Session Jacques Fellay EPFL, Lausanne, Switzerland

Washington D.C., USA, July 2012www.aids2012.org The A Team Galit Alter Irene Onyango Morgane Rolland Jason Brenchley Hendrik Streeck

Washington D.C., USA, July 2012www.aids2012.org Hot Topics 1.Reservoirs & latency 2.Inflammation & fibrosis 3.Genomics & systems biology

Washington D.C., USA, July 2012www.aids2012.org Hot Topics 1.Reservoirs & latency 2.Inflammation & fibrosis 3.Genomics & systems biology

Washington D.C., USA, July 2012www.aids2012.org Viral Eradication: The Cure Agenda AIDS Research Institute (IrsiCaixa) Autonomous University of Barcelona (UAB) Catalan Institution for Research and Advanced Studies (ICREA) Javier Martinez-Picado

Washington D.C., USA, July 2012www.aids2012.org Strategies to cure HIV Treatment optimization & intensification (eliminate all replication) Reversal of HIV latency (increase viral production) Immune-based therapies (reverse pro-latency signaling) Therapeutic vaccination (to enhance host-control) Gene therapy

Washington D.C., USA, July 2012www.aids2012.org Strategies for depleting the latent HIV reservoir Nanoparticle targeting of CD4+ T cells (Jerome Zack) Allogeneic bone marrow transplantation (Timothy Henrich)

Washington D.C., USA, July 2012www.aids2012.org Nanoparticles and new PKC activators (Jerome Zack) Targeting lipid nanoparticles to CD4 T cells Loading them with activators of latent virus expression + anti-HIV drug to inhibit viral spread  Reactivates latently infected cells, minimizes bystander activation and renders new virus non-infectious

Washington D.C., USA, July 2012www.aids2012.org The Structure of Rat Liver Vault at 3.5 Angstrom Resolution Tanaka et al. Science 323, 384 (2009)

Washington D.C., USA, July 2012www.aids2012.org Long-Term Reduction in Peripheral Blood HIV-1 Reservoirs Following Reduced-Intensity Allogeneic Stem Cell Transplantation in Two HIV- Infected Individuals Timothy J. Henrich 1,2, Gaia Sciaranghella 3, Jonathan Z. Li 1,2, Sebastien Gallien 4, Vincent Ho 5,2, Ann S. LaCasce 5,2, and Daniel R. Kuritzkes 1,2 1 Brigham and Women's Hospital, Boston, MA; 2 Harvard Medical School, Boston, MA; 3 Ragon Institute of MGH, MIT, and Harvard, Boston, MA; 4 Hopital Saint-Louis, Paris, France; 5 Dana-Farber Cancer Institute, Boston, MA. Your logo

Washington D.C., USA, July 2012www.aids2012.org Patient A Viral outgrowth assay negative day No 2-LTRs detected

Washington D.C., USA, July 2012www.aids2012.org Allogeneic HSCT with suppressive ART led to a sustained reduction in the HIV-1 reservoir in PBMCs What is now required to fully assess the extent of HIV-1 reservoir reduction?  Tissue sampling  Analytic treatment interruption

Washington D.C., USA, July 2012www.aids2012.org Hot Topics 1.Reservoirs & latency 2.Inflammation & fibrosis 3.Genomics & systems biology

Inflammation ↑ Endothelium adhesion ↑ Monocyte activation Dyslipidemia Hypercoagulation/ thrombotic events Endothelial dysfunction Inflammation ↑ Endothelium adhesion ↑ Monocyte activation Dyslipidemia Hypercoagulation/ thrombotic events Endothelial dysfunction Microbial translocation HIV-associated fat Metabolic syndrome HIV production HIV replication CMV Excess pathogens HIV-mediated loss of regulatory cells (Tregs) Steve Deeks

Washington D.C., USA, July 2012www.aids2012.org Lymph Node Fibrosis (Timothy Schacker) Inflammation  loss of FRC network in T cell zone of lymph nodes  decrease in IL-7 production  CD4 T cell apoptosis  collagen deposition Zeng et al., PLoS Pathog. 2012

Washington D.C., USA, July 2012www.aids2012.org Lymph node fibrosis is similar in HIV- individuals in Uganda and in chronic HIV+ individuals in the US  may account for lower baseline CD4+ T cells and less immune reconstitution with ART  may modify the size of the reservoir  may have implications for eradication and cure in the developing world

Washington D.C., USA, July 2012www.aids2012.org Hot Topics 1.Reservoirs & latency 2.Inflammation & fibrosis 3.Genomics & systems biology

Washington D.C., USA, July 2012www.aids2012.org The future of genomics in HIV medicine Francis Collins – an NIH perspective Philip Tarr – a clinician’s perspective  Genomics has the potential to benefit researchers, clinicians and patients

Washington D.C., USA, July 2012www.aids2012.org Third generation long-read sequencing of HIV-1 transcripts discloses cell type specific and temporal regulation of RNA splicing Frederic Bushman International AIDS Meeting Washington DC, 2012

Washington D.C., USA, July 2012www.aids2012.org Combination of two technological advances to explore HIV transcripts at an unprecedented scale: –Single molecule microdroplet-based digital PCR technology (RainDance) –High-throughput single molecule real-time sequencing technology (Pacific Bioscience)

Complete message population of HIV in CD4 + T cells 77 complete message structures Evidence for 36 additional transcripts from partial reads Total: 113 mRNAs 19 novel transcripts including a new completely spliced class (~1kb) Scott Sherrill-Mix

Washington D.C., USA, July 2012www.aids2012.org A web site for exploring HIV Systems Biology data Be a systems biologist!

Washington D.C., USA, July 2012www.aids2012.org Track A Committee Danny Douek Amalio Telenti Galit Alter Frederic Bushman Nicolas Chomont Genoveffa Franchini David Haerry Esper Kallas Yves Levy Sharon Lewin Thumbi Ndung’u Robert Oelrichs Javier Martinez-Picado

Washington D.C., USA, July 2012www.aids2012.org Science