Individualized HIV curative combination strategy against persistent HIV on art

Active Cooperative Agreement Awarded Last action

Award ID
UM1AI191272
Recipient
Awarding agency
Obligated
$6,938,197

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 27% complete
Place of performance
Philadelphia, PA 19104, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
We have demonstrated multiple lines of evidence supporting the role for autologous neutralizing antibodies (ANABS) to restrict virus rebound. The positive relationship between anab suppression of virus reactivation EX vivo and time to rebound in vivo indicates that ANABS are a strong host determinant in the suppression of the HIV viral reservoir. This offers a unique opportunity to develop an individualized HIV cure strategy targeting the anab-resistant component of the HIV reservoir that is not controlled by the host upon reactivation. Taking advantage of the full complement of immune responses (i.e., a combination of innate, humoral and cell-mediated components), this proposal seeks to develop an individually tailored strategy that will bring together a) neutralizing antibody responses enhanced via mrna-lipid nanoparticle (LNP) technology, B) anab-resistant HIV ENV HLA-E restricted adaptive NK cells or creation of multi-specific molecules targeting the HIV loaded HLA-E MHC complex, and C) engineered cell-mediated effector strategies, consisting of multivalent car T cells and CD64-transduced NK cells with a membrane-bound combinations of broadly neutralizing antibodies optimized against the anab-resistant reservoir of each participant. Our preliminary data indicates that each of the strategies proposed has potential for antiviral control, supporting their inclusion in the combined approach proposed. Our central hypothesis is that characterization of the anab-resistant HIV reservoir will permit development of a targeted, personalized combination strategy of antiviral innate, humoral and cell-mediated responses, which together will elicit sustained viral control and/or viral eradication. To test this hypothesis, we will first conduct comprehensive reservoir screens in persons with HIV suppressed on art after early or late art initiation (to evaluate strategies against distinct levels of reservoir diversity) to identify sequences of anab-resistant reservoir viruses which will be used to generate individual tailored ANABS (induced by mrna-LNP-based vaccination) and, concurrently, to identify the best combination of existing broadly neutralizing antibodies (BNABS) that can achieve virus control. Second, we will build personalized cell-mediated responses to clear infected cells by (I) HLA-E responsive ENV peptides for adaptive NK cell generation, (II) phage display targeting for BI/TRI-specific HLA-E- ENV peptide complex engagers, and (III) individually defined bnab combinations loaded on to CD64-NK or expressed as TRI-bnab constructs on car T cells. To facilitate future clinical deployment of this combined immune strategy, we will develop personalized virus reactivation strategies, wherein individual's CD4+ cells bearing integrated HIV will be characterized to design personalized LRA approaches optimized to maximize HIV reactivation. Together with significant institutional and industry commitment, our proposal brings together collaborative groups from accelevir, merck, acuitas therapeutics, biontech, bluewhale BIO, cytoimmune therapeutics, george washington univ., univ. Of nebraska, ragon institute, massachusetts institute of technology, duke univ., philadelphia fight johns hopkins univ., univ. Of pennsylvania, and wistar institute.

Transactions

Action Obligated Date
Amendment $3,369,553
Original award $3,568,644

Subawards

Subrecipient Amount Awarded
Duke University Prof. Wagh’s research for this project will involve providing computational analyses for vaccine design, analyses of immune responses and within-host Env… $134,584
The Trustees Of The University Of Pennsylvania As the director of the clinical aspect of this project, I will oversee all clinical activities and contribute to scientific discussions post-laboratory studies.… $405,212
Duke University Most current strategies aiming to control or eradicate HIV rely on harnessing effector functions of cytotoxic T cells and/or antibodies to attack HIV and… $323,000
Massachusetts Institute Of Technology To isolate single chain fragment variables (scFvs) that recognize HIV peptides presented by HLA-E, develop bi-specific NK engagers and CAR-NK cells, and… $358,438
The General Hospital Corporation The Lichterfeld and Yu lab will conduct multidimensional single-cell assays with isolated CD4 T cells from ART-treated study participants to investigate the… $453,750
The Trustees Of The University Of Pennsylvania As the director of the clinical aspect of this project, I will oversee all clinical activities and contribute to scientific discussions post-laboratory studies.… $165,208
Philadelphia Fight Philadelphia FIGHT (Site PI/Co-I: Karam Mounzer MD) will conduct EMR and paper chart reviews to pre-screen participants for eligibility in the study.… $90,526
The Trustees Of The University Of Pennsylvania For this proposal, Dr. Bar and her personnel will work with the Weissman lab to support the aims of RF1, including sequencing env, generating Env clones and… $683,856
The Johns Hopkins University The Siliciano lab is developing a comprehensive reservoir screening method that can be used to identify HIV-1, SIV, and SHIV variants that are resistant to… $453,548
George Washington University (The) The hypothesis of this proposal is that LRA-driven HIV expression on ART, in the presence of autologous neutralizing antibodies, will generate otherwise… $349,916

Quick answers

Who received award UM1AI191272?

UM1AI191272 was awarded to The Wistar Institute Of Anatomy And Biology by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on July 7, 2025.

How much is award UM1AI191272 worth?

$6,938,197 has been obligated on UM1AI191272.

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