Hope - HIV obstruction by programmed epigenetics

Active Cooperative Agreement Awarded Last action

Award ID
UM1AI164559
Recipient
Awarding agency
Obligated
$59,575,926

Award facts

Completion date 74% complete
Originally
Funding
  • $54,239,900.00 Federal
  • $5,336,026.00 Non-federal
Funding agency
National Institute of Neurological Disorders and Stroke National Institutes of Health, Department of Health and Human Services
Place of performance
San Francisco, CA 94158, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
/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.

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Subawards

Subrecipient Amount Awarded
The Feinstein Institutes For Medical Research Dr. Nixon is a Professor and Director of the Institute for Translational Research at the Feinstein Institutes for Medical Research (FIMR) and as a research… $1,415,473
Fundacao Faculdade De Medicina Dr. Kallas and the team of investigators in Brazil aim to identify whether exposure to spironolactone impact HIV reservoir and to foster liaisons between cure… $330,953
University Of Florida • We will investigate the role of p32 and TRIM43 in the transcriptional regulation of HIV. • In collaboration with Cedric Feschotte we will optimize… $3,048,250
Makerere University Walter Reed Program LIMITED Under this proposal, Dr. Mwesigwa and the Makerere University Walter Reed Project (MUWRP) team will be responsible for the following: - Submitting RV419… $180,322
San Francisco Aids Foundation The research coordinator will establish the San Francisco CAB guidelines to support selection of members who are motivated, qualified, and experienced. They… $116,010
Yale Univ For this proposal, Priti Kumar from Yale School of Medicine, who has intensive expertise and experience in humanized mouse models, will work with the members of… $2,205,681
Leibniz-Institut Fur Virologie The principal goal of this project is to develop strategies to epigenetically silence and subsequently inactivate the excise HIV-1 provirus. $739,619
Lakehead University Dr. Sameshima will oversee the Community Arts Integrated Research activities of the HOPE MDC, in collaboration with Dr. Defechereux. Specifically, Dr. Sameshima… $78,575
Cornell University This is a subcontract that is part of a UM1 proposal for the Martin Delaney Collaboratories to Cure HIV, entitled HOPE for “HIV Obstruction by… $1,265,486
Yale Univ The Glazer lab will design and synthesize peptide nucleic acids (PNAs) to target the HIV genome. The molecules will be designed in collaboration with Dr. Kumar,… $67,000
The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Dr Hsu and AFRIMS team will perform a pharmacokinetics study in rhesus macaques to determine the pharmacokinetic properties, oral bioavailability and toxicity… $883,033
The Regents Of The University Of California This proposal focuses on developing a new treatment for HIV based on delivering Brec1, PNAs and base editors. For this proposal the Murthy laboratory will… $1,409,156
The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. The goal of this work is to develop a better understanding of the distribution of HIV reservoirs throughout the many compartments of the body outside of the… $567,060
University Of California, San Diego Most HIV anatomical reservoirs are hard to reach but studying blood alone is not enough to fully characterize the HIV reservoirs. Thus, we will leverage prior… $564,046
Buck Institute For Research On Aging For this study, de-identified healthy donor blood will be obtained from Vitalant (San Francisco) and primary CD4 T cells will be isolated by Verdin lab… $1,974,039
Weill Medical College Of Cornell University Our site will increase one staff members effort and include reagents to conduct HIV reservoir measures from retrospective biospecimens from HOPE US based… $5,040,629
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Quick answers

Who received award UM1AI164559?

UM1AI164559 was awarded to J.david Gladstone Institutes by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 16, 2021.

How much is award UM1AI164559 worth?

$59,575,926 has been obligated on UM1AI164559: $54,239,900 in federal funding and $5,336,026 in non-federal funding.

Which agency awarded UM1AI164559?

National Institute of Allergy and Infectious Diseases (National Institutes of Health) awarded UM1AI164559, with funding from National Institute of Neurological Disorders and Stroke (National Institutes of Health).

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