track a rapporteur team
DESCRIPTION
Track A Rapporteur Team. Dr. Nilu Goonetilleke. Dr. Zabrina Brumme. Dr. Matthew Parsons. Dr. Mark Brockman. Dr. Jenniffer Maroa. Dr. Renee van der Sluis. A new era in our fight against HIV: the possibility of a world without AIDS. - PowerPoint PPT PresentationTRANSCRIPT
Slide 1
Track A Rapporteur Team
Dr. Jenniffer MaroaDr. Matthew ParsonsDr. Renee van der Sluis
Dr. Mark Brockman
Dr. Nilu Goonetilleke
Dr. Zabrina Brumme
1
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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Nuclear Export
Transla3on
Assembly
Budding
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TRIM5
Release
Tetherin
OAS1/RNaseL
PKR ISG20
APOBEC
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Tracking TRIM22
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