Enhancing engineered T cell therapies for HIV through binder discovery and receptor design
Active Project Grant Awarded Last action
- Award ID
- F31AI197985
- Recipient
-
The Regents Of The University Of California. San Francisco UEI KMH5K9V7S518
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $86,194
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 2% complete
- Originally
- Place of performance
- San Francisco, CA 94143, USA
Award details come from USAspending.gov.
Description
- Abstract
- Human immunodeficiency virus (HIV) is an infection for which there is no cure. Studies of rare individuals who control HIV either spontaneously or after stopping antiretroviral therapy (including those by proposal sponsor, professor rachel rutishauser) suggest that robust HIV-specific CD8+ T cell responses may promote durable control of the virus. RE-directing T cells to target HIV ENV on the surface of infected cells via introduction of an engineered T cell receptor represents one avenue for generating effective anti-HIV T cell responses in individuals who otherwise do not control the infection. However, approaches to engineer anti-HIV T cells to date have not shown consistent efficacy, perhaps due to limitations of current chimeric antigen receptor (car) architectures. Furthermore, IT remains unclear how to optimally target HIV ENV with an engineered T cell because very few potential binders have been tested, and viral escape has not been assessed. Leveraging several T cell engineering advances pioneered in the context of cancer by the CO-sponsor of this application, professor justin eyquem, preliminary data has demonstrated that a more sensitive receptor architecture can detect and kill HIV- infected cells more efficiently than conventional car T cells. This proposal seeks to build on this finding by identifying optimal binder domains for use in an engineered HIV T cell receptor therapy, that best eliminate infected cells and mitigate HIV escape. In specific aim 1, broadly-neutralizing antibody (BNAB)-derived binders will be assayed through large in vitro parallel characterizations, or "pooled screens," wherein 200 different bnabs will be compared. Top binders will be identified by performance across assays measuring polyfunctionality by T cell proliferation, activation, cytokine production, and chronic stimulation. The top 9 BNAB binders will then be tested individually for therapeutic efficacy in vivo using an established humanized mouse model of HIV. In specific aim 2, viral escape will be characterized from individual BNAB binders covering each BNAB class, and binder combinations to mitigate escape will then be explored in a novel, dual-epitope targeting receptor. The primary hypothesis of this proposal is that optimal binder domains for anti-HIV T cell therapies must target accessible and evolutionarily conserved epitopes on HIV ENV to mount an effective antiviral response while mitigating viral escape. Successful completion of this proposal will decode the rules governing optimal, anti-HIV engineered T cell receptor design, towards the goal of generating T cell therapies potent enough to control or eliminate the virus in vivo. This research project will be conducted at a top research institution with a rich training environment, the university of california, SAN francisco (UCSF). The proposed sponsors, additional mentors, and training plan to develop the applicant's technical and professional toolkit will aide in the successful completion of this research proposal and in the development of the skills necessary for a career as an independent biomedical researcher.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $43,097 | |
| Amendment | $0 | |
| Original award | $43,097 |
Quick answers
Who received award F31AI197985?
F31AI197985 was awarded to The Regents Of The University Of California. San Francisco by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on October 15, 2026.
How much is award F31AI197985 worth?
$86,194 has been obligated on F31AI197985.
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