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Track A Rapporteur Team

Dr. Jenniffer MaroaDr. Matthew ParsonsDr. Renee van der Sluis

Dr. Mark Brockman

Dr. Nilu Goonetilleke

Dr. Zabrina Brumme

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Slide credit: Dr. Anthony FauciBreathtaking advances in treatment and prevention allow us to consider the possibility of a world without AIDS - Anthony Fauci

An HIV cure is possible - Jintanat Ananworanich

The AIDS free world that many of you have worked for so long to build is just over the horizon President Bill ClintonA new era in our fight against HIV: the possibility of a world without AIDS

Plasma viral rebound in the Mississippi Child after 27 months of remission

-> provides definitive proof of how early the reservoir is seeded in HIVHIV latency, reservoirs and eradication: challenges and complexitiesMelissa ChurchillDeborah PersaudAnatomical HIV reservoirs may differ in their relevance to the pathogenesis of latency, and their ability to be safely eliminated

Carine van LintComplex epigenetic and non-epigenetic mechanisms of viral latency

Nicolas ChomontExtraordinary 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

Sarah Palmer- challenges in quantifying the latent reservoir and assessing replication competence

- novel, standardized methods are urgently neededImage credit: Sarah PalmerChomont et al. Nat Med 2009HIV latency, reservoirs and eradication: challenges and complexitiesCombination approach to sustained HIV remissionEarly HAART

-> reduce seeding of the reservoir & stack the deck in favor of eradication-Reactivate reservoir with anti-latency agents

Eliminate CCR5+ cells by gene therapy

Boost humoral and T-cell immunity via vaccines/immunotherapiesCombination kick and killImage: Ole Sgaard; quote: Anthony Fauci5Romidepsin treatment for latency reactivation: AIDS 2014 breakthrough

pVL (copies/ml)Days post-infection

Ole Sgaard

Phase I/II nonrandomized trial (N=6): HDAC inhibitor romidepsin safely activated latently infected cells and induced transient quantifiable plasma viremia

6An alternative to kick and kill:Latency maintenance via permanent silencing

Eric Verdin

Kazuo Suzuki

Short hairpin RNAs targeting the HIV-1 promotor region as a strategy to sustain latency Hiromi ImamichishRNA library screen identified host proteins/pathways that contribute to latency modulation

mTOR pathway inhibitors blocked reactivation from viral 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.7

Jake Estes:Sensitive in situ detection of SIV vRNA and vDNAUseful to examine -viral reservoirs-anatomical location of latent genomesBrandon Keele:Ultra-deep barcoded SIVmac239 to identify and quantify viral reservoirsAdvances in tracking individual viral genomes to study reservoirs

~10,000 unique variants in stockInfect at high MOI (~1000 unique founder viruses)Useful tool to test various remission/cure strategies in NHPs

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 accelerate antibody evolution via sequential, iterative vaccination with evolving envelope antigens. Dr. Anthony Fauci; Dr. Antonio Lanzavecchia

UCA with long CDR H3mature BnAbUCAmature BnAb(high somatic mutation)YEARSMONTHSPenny Moore:Challenge: Nab developmental pathways differ by epitopeCD4bs NAbs-Highly mutated away from common ancestor-Maturation takes yearsV1V2 NAbsRequires B-cell receptor with a long CDR H3 these are very rareLiao et al Nature 2013Doria-Rose et al Nature 2014Jia Guo:

A single-gene bi-specific immunoadhesinRichard 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 domainsEngineered antibodies for treatment & prevention: improving on nature

SG-bispecific IAPGT1285A8PGT1285A8Encodes PGT128 (anti-glycan-V3) and Hu5A (anti-CD4) neutralized 100% of viral isolates tested.

HIV-infected CD4 T-cellCD8 T-cell (not HIV-specific)Anti-CD3 scFvHIV envCD3KILLVRC07-FabJonah Sacha: RhCMV SIV 68-1 vaccine update: protection by MHC-E Restricted CD8+ T cells-> MHC-E restricted CD8+ T cells recognize SIV infected cells-> completely novel immune response against HIV

64% of the total RhCMV/gag-elicited CD8+ T cell responses were MHC-II-restricted! Science 2013

MHC-IMHC-IIMHC-IMHC-IIRhCMV/SIV vector 68-1 induced CD8+ T cells are MHC-E restrictedMHC-Enot determinedAdvances in HIV virology: host restriction factors Federica Gnudi: MX2 rs2074560 G/G genotype associated with reduced HIV-1 replication in vitro and protection from HIV infection in vivoMX2Matthew Woods:HERC5 interferes with REV/RRE-mediated nuclear export of HIV RNAHERC5MARCH8Kenzo Tokunaga:Novel restriction factor MARCH8 blocks envelope incorporation into the virion, thereby reducing viral infectivityThe tissue is the issue: moving immunology beyond the bloodJake Estes:After 20 weeks of suppressive cART in an SIV model:persistent low-level viral production in lymphoid tissuesIncomplete reversal of GI damage sustained immune activation

Pre-cARTPost-cART

Genital and GI immunology: novel correlates of HIV acquisitionShaheed Abdulhaqq

HIV-exposedseronegative female sex workers express high levels of IFN in cervical epithelium

150 mIFNGodfrey Kigozi

Presence of IL-8, MIG, GM-CSF in foreskin associated with increased risk of HIV seroconversion

Potential for novel microbicides or topical anti-inflammatories for prevention?

HIV-exposed seronegative MSM overexpress antiproteases in rectal mucosa. Laura Romas:

AP 1ControlHESNGenital and GI immunology: towards novel interventions% uninfectedWeeks after SIV challenge47controlp=0.002Alexandra Ortiz% incidence-freeDays after infectionp=0.03Pb+IL21+ARVARV onlyTreatment with probiotics and IL21 reduced disease progression and gut pathology in ARV-treated macaquesBlockade of the 47 integrin delays vaginal SIV acquisitionFrancois VillingerReversing chronic immune activation in HIV: a role for HDACi?Anne Sofie Kjr Phase I/II nonrandomized trial:

Treatment with HDAC inhibitor Panobinostat significantly reduces markers of inflammation and coagulation in chronic HIV infectionHighlights potential role for certain HDAC inhibitors as anti-inflammatory agents

Christian ApetreiHDAC inhibitor romidepsin enhanced virus replication and T-cell immune activation in a novel SIV model system

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 infectionThe city of Vancouver looks forward to welcoming you to IAS 2015

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