Track A Rapporteur Team

1. Track A Rapporteur Team Dr. NiluGoonetilleke Dr. Zabrina Brumme Dr. Matthew Parsons Dr. Mark Brockman Dr. JennifferMaroa Dr. Renee van derSluis

2. A new era in our fight against HIV: the possibility of a world without AIDS • “Breathtaking advances in treatment and prevention allow us to consider the possibility of a world without AIDS” - Anthony Fauci • “An HIV cure is possible” - JintanatAnanworanich • “The AIDS free world that many of you have worked for so long to build is just over the horizon” – President Bill Clinton Slide credit: Dr. Anthony Fauci

3. HIV latency, reservoirs and eradication: challenges and complexities Melissa Churchill Deborah Persaud Carine van Lint Plasma viral rebound in the “Mississippi Child” after 27 months of remission -> provides definitive proof of how early the reservoir is seeded in HIV Anatomical HIV reservoirs may differ in their relevance to the pathogenesis of latency, and their ability to be safely eliminated Complex epigenetic and non-epigenetic mechanisms of viral latency

4. HIV latency, reservoirs and eradication: challenges and complexities Nicolas Chomont Sarah Palmer • Extraordinary heterogeneity of T cell subsets in terms of: • their contribution to the total reservoir • their longevity of persistence • their susceptibility to reactivation by therapeutic approaches - challenges in quantifying the latent reservoir and assessing replication competence - novel, standardized methods are urgently needed Image credit: Sarah Palmer Chomont et al. Nat Med 2009

5. Combination approach to sustained HIV remission Early HAART -> reduce seeding of the reservoir & “stack the deck” in favor of eradication Combination “kick and kill” • -Reactivate reservoir with anti-latency agents • Eliminate CCR5+ cells by gene therapy • Boost humoral and T-cell immunity via vaccines/immunotherapies Image: Ole Søgaard; quote: Anthony Fauci

6. Romidepsin treatment for latency reactivation: AIDS 2014 breakthrough Ole Søgaard Phase I/II nonrandomizedtrial (N=6): HDAC inhibitor romidepsinsafelyactivatedlatentlyinfectedcells and induced transient quantifiable plasma viremia pVL (copies/ml) Days post-infection

7. An alternative to “kick and kill”: Latency maintenance via permanent silencing Eric Verdin shRNA library screen identified host proteins/pathways that contribute to latency modulation mTOR pathway inhibitors blocked reactivation from viral latency Hiromi Imamichi Kazuo Suzuki Short hairpin RNAs targeting the HIV-1 promotor region as a strategy to sustain latency Persistent release of HIV transcripts from infected cells harboring defective proviruses during HAART -> driver of chronic immune activation? -> if so, need interventions to block this.

8. Advances in tracking individual viral genomes to study reservoirs • Jake Estes: • Sensitive in situ detection of SIV vRNA and vDNA • Brandon Keele: • Ultra-deep barcoded SIVmac239 to identify and quantify viral reservoirs Infect at high MOI (~1000 unique founder viruses) ~10,000 unique variants in stock Useful to examine -viral reservoirs -anatomical location of latent genomes Useful tool to test various remission/cure strategies in NHPs

9. Advances in vaccine research:Eliciting neutralizing antibodies via “B-cell lineage vaccine design” Natural infection: dynamic co-evolution of virus and host drives the emergence of antibody neutralization breadth over a period of months to years B-cell lineage vaccine design: recapitulate and accelerateantibody evolution via sequential, iterative vaccination with evolving envelope antigens. Dr. Anthony Fauci; Dr. Antonio Lanzavecchia

10. Penny Moore:Challenge: Nab developmental pathways differ by epitope V1V2 NAbs Requires B-cell receptor with a long CDR H3 – these arevery rare CD4bs NAbs -Highly mutated away from common ancestor -Maturation takes years mature BnAb UCA with long CDR H3 UCA mature BnAb (high somatic mutation) YEARS MONTHS Doria-Roseet al Nature 2014 Liao et al Nature 2013

11. Engineered antibodies for treatment & prevention: ‘improving on nature’ Richard Koup: Non HIV-specific CD8 T cells in germinal centers can be harnessed to kill HIV-infected CD4+ T-cells using bispecific antibodies containing anti-CD3 and anti-gp120 domains • JiaGuo: • A single-gene bi-specific immunoadhesin CD8 T-cell (not HIV-specific) HIV-infected CD4 T-cell KILL VRC07-Fab Anti-CD3 scFv PGT128 PGT128 • Encodes PGT128 (anti-glycan-V3) and Hu5A (anti-CD4) • neutralized 100% of viral isolates tested. HIV env 5A8 5A8 CD3 SG-bispecificIA

12. Jonah Sacha: RhCMV SIV 68-1 vaccine update: protection by MHC-E Restricted CD8+ T cells Science 2013 MHC-I MHC-II 64% of the total RhCMV/gag-elicited CD8+ T cell responses were MHC-II-restricted! RhCMV/SIV vector 68-1 induced CD8+ T cells are MHC-E restricted MHC-I MHC-II MHC-E not determined -> MHC-E restricted CD8+ T cells recognize SIV infected cells -> completely novel immune response against HIV

13. Advances in HIV virology: host restriction factors Kenzo Tokunaga: Novel restriction factor MARCH8 blocks envelope incorporation into the virion, thereby reducing viral infectivity MARCH8 MX2 HERC5 Matthew Woods: HERC5 interferes with REV/RRE-mediated nuclear export of HIV RNA Federica Gnudi: MX2 rs2074560 G/G genotype associated with reduced HIV-1 replication in vitro and protection from HIV infection in vivo

14. “The tissue is the issue”: moving immunology beyond the blood • Jake Estes: • After 20 weeks of suppressive cART in an SIV model: • persistent low-level viral production in lymphoid tissues • Incomplete reversal of GI damage • sustained immune activation Post-cART Pre-cART

15. Genital and GI immunology: novel correlates of HIV acquisition ShaheedAbdulhaqq HIV-exposed seronegative female sex workers express high levels ofIFNε in cervical epithelium Laura Romas: Godfrey Kigozi Presence of IL-8, MIG, GM-CSF in foreskin associated with increased risk of HIV seroconversion HIV-exposed seronegative MSM overexpressantiproteases in rectal mucosa. 150 μm AP 1 IFNε Control HESN Potential for novel microbicides or topical anti-inflammatories for prevention?

16. Genital and GI immunology: towards novel interventions Alexandra Ortiz Francois Villinger Blockade of the α4β7 integrin delays vaginal SIV acquisition Treatment with probiotics and IL21 reduced disease progression and gut pathology in ARV-treated macaques Pb+IL21+ARV α4β7 % incidence-free % uninfected control ARV only p=0.03 p=0.002 Days after infection Weeks after SIV challenge

17. Reversing chronic immune activation in HIV: a role for HDACi? Anne SofieKjær Christian Apetrei Phase I/II nonrandomized trial: Treatment with HDAC inhibitor Panobinostat significantly reduces markers of inflammation and coagulation in chronic HIV infection HDAC inhibitor romidepsinenhanced virus replication and T-cell immune activation in a novel SIV model system Highlights potential role for certain HDAC inhibitors as anti-inflammatory agents

18. Summary and conclusions AIDS 2014 Track A featured exciting advances in HIV cure and vaccine research, as well as basic and translational research in the immunovirology of HIV/SIV infection The city of Vancouver looks forward to welcoming you to IAS 2015