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Track A – BASIC SCIENCE

Track A – BASIC SCIENCE. Rapporteur Session Jacques Fellay EPFL, Lausanne, Switzerland. The A Team. Jason Brenchley. Irene Onyango. Galit Alter. Morgane Rolland. Hendrik Streeck. Hot Topics. R eservoirs & latency Inflammation & fibrosis Genomics & systems biology. Hot Topics.

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Track A – BASIC SCIENCE

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  1. Track A – BASIC SCIENCE Rapporteur Session Jacques Fellay EPFL, Lausanne, Switzerland

  2. The A Team Jason Brenchley Irene Onyango Galit Alter Morgane Rolland HendrikStreeck

  3. Hot Topics • Reservoirs & latency • Inflammation &fibrosis • Genomics & systems biology

  4. Hot Topics • Reservoirs & latency • Inflammation &fibrosis • Genomics & systems biology

  5. Viral Eradication: The Cure Agenda Javier Martinez-Picado AIDS Research Institute (IrsiCaixa) Autonomous University of Barcelona (UAB) Catalan Institution for Research and Advanced Studies (ICREA)

  6. Strategies to cure HIV Treatment optimization & intensification Gene therapy (eliminate all replication) Therapeutic vaccination Reversal of HIV latency (to enhance host-control) (increase viral production) Immune-based therapies (reverse pro-latency signaling)

  7. Strategies for depleting the latent HIV reservoir • Nanoparticle targeting of CD4+ T cells (Jerome Zack) • Allogeneic bone marrow transplantation (Timothy Henrich)

  8. 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

  9. The Structure of Rat Liver Vault at 3.5 Angstrom Resolution Tanaka et al. Science 323, 384 (2009)

  10. Your logo Long-Term Reduction in Peripheral Blood HIV-1 Reservoirs Following Reduced-Intensity Allogeneic Stem Cell Transplantation in Two HIV-Infected Individuals Timothy J. Henrich1,2, Gaia Sciaranghella3, Jonathan Z. Li1,2, Sebastien Gallien4, Vincent Ho5,2, Ann S. LaCasce5,2, and Daniel R. Kuritzkes1,2 1Brigham and Women's Hospital, Boston, MA; 2Harvard Medical School, Boston, MA; 3Ragon Institute of MGH, MIT, and Harvard, Boston, MA; 4 Hopital Saint-Louis, Paris, France; 5Dana-Farber Cancer Institute, Boston, MA.

  11. Patient A Viral outgrowth assay negative day +1266 No 2-LTRs detected

  12. 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

  13. Hot Topics • Reservoirs & latency • Inflammation &fibrosis • Genomics & systems biology

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

  15. 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

  16. 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

  17. Hot Topics • Reservoirs & latency • Inflammation &fibrosis • Genomics & systems biology

  18. 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

  19. 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

  20. 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)

  21. Complete message population of HIV-189.6 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

  22. A web site for exploring HIV Systems Biology data http://microb32.med.upenn.edu/ Be a systems biologist!

  23. Track A Committee Danny Douek Amalio Telenti Galit Alter Frederic Bushman Nicolas Chomont GenoveffaFranchini David Haerry EsperKallas Yves Levy Sharon Lewin ThumbiNdung’u Robert Oelrichs Javier Martinez-Picado

  24. Science

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