HOPE - HIV Obstruction by Programmed Epigenetics

Information

  • Research Project
  • 10313946
  • ApplicationId
    10313946
  • Core Project Number
    UM1AI164559
  • Full Project Number
    1UM1AI164559-01
  • Serial Number
    164559
  • FOA Number
    RFA-AI-20-035
  • Sub Project Id
  • Project Start Date
    8/16/2021 - 2 years ago
  • Project End Date
    4/30/2026 - a year from now
  • Program Officer Name
    NOVAK, LEIA KAYE
  • Budget Start Date
    8/16/2021 - 2 years ago
  • Budget End Date
    4/30/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
  • Award Notice Date
    8/13/2021 - 2 years ago

HOPE - HIV Obstruction by Programmed Epigenetics

PROJECT SUMMARY/ABSTACT After 40 years, a cure for people living with HIV (PLWH) remains both elusive and one of NIAID/NIH?s highest priorities. Rebound-competent latent reservoir cells persist despite antiretroviral therapy and rekindle infection due to the lack of efficient proviral silencing. The underlying hypothesis of the HIV Obstruction by Programmed Epigenetics (HOPE) Collaboratory application is a novel ?block-lock-excise? approach?that entails the long-term durable silencing of viral expression towards permanent excision of the latent provirus?will lead to the permanent control of the virus in the absence of therapy. A graded transformation of remnant HIV in PLWH is proposed from latent into silent to permanently defective proviruses, thus emulating and accelerating the natural path that human endogenous retroviruses have taken in the human genome over millions of years. This hypothesis was formulated on the basis of 30+ years of dedicated research by HOPE investigators into the underlying mechanisms of HIV latency, lack of success to date with latency-reversing strategies, recent results with Tat inhibitor didehydro-Cortistatin A (dCA) and ELITE controllers showing that a successful ?functional? HIV cure could arise if there is a deep silencing of reservoir virus, and the availability of advanced genome- engineering technologies (Brec1 recombinase, peptide nucleic acids, CRISPR-base editors) for direct delivery of the final coup de grace: excision of remnant virus for permanent cure. The central hypothesis will be tested in three Research Focuses (RFs) and five central objectives shared between the three RFs. Specific Aim (RF) 1: Define mechanistically the durable transcriptional silencing of HIV across all T- and myeloid cell subsets by combinatorial targeting of key host and viral factors. Specific Aim (RF) 2: Develop and characterize next- generation HIV silencing approaches in the control of HIV rebound. Specific Aim (RF) 3: Disable the silenced HIV-1 provirus by targeted genome engineering. Objective 1: Determine the epigenetic architecture of the integrated provirus at different integration sites that prevents permanent silencing of latent HIV. Objective 2: Define, at the molecular level, cell types and epigenetic cell states that favor viral rebound. Objective 3: Identify molecular functions of Tat and host factors that prevent permanent silencing. Objective 4: Learn from HERV silencing and mutational decay in the human genome. Objective 5: Respond to community expectations around ?functional? and ?classical? cure approaches. The HOPE Collaboratory partnered with the San Francisco AIDS Foundation to build a strong art-based community education program and with three primary industry leaders, Amgen, Sangamo and Constellation, who will provide intellectual and materialistic support. We also engaged with four clinical cohorts of PLWH for clinical sample analysis in the US, Brazil and Africa. Collectively, the innovative science, renowned members, collaborative organizational structure and milestone- driven research plan of the HOPE Collaboratory represents a new and substantive departure from the status quo and promises a fundamental new approach to HIV Cure strategies.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    UM1
  • Administering IC
    AI
  • Application Type
    1
  • Direct Cost Amount
    4097794
  • Indirect Cost Amount
    1238232
  • Total Cost
    5336026
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:5336026\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZAI1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    J. DAVID GLADSTONE INSTITUTES
  • Organization Department
  • Organization DUNS
    099992430
  • Organization City
    SAN FRANCISCO
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    941582261
  • Organization District
    UNITED STATES