Optimizing engineered t cells with highly sensitive anti-HIV/ENV HLA-independent t cell receptors (hits)

The National Institute of Allergy and Infectious Diseases awarded The Regents of the University of California, San Francisco $3.33 million on July 9, 2026, to optimize engineered T cells with highly sensitive anti-HIV/envelope HLA-independent T cell receptors (HITS) under the Allergy and Infectious Diseases Research program (CFDA 93.855).

The research directly applies T cell engineering advances developed in cancer immunotherapy to chronic HIV infection. The project addresses limitations in current engineered T cell therapies for HIV, including random integration events that pose malignant transformation risk, short lifespan, and failure of traditional chimeric antigen receptors to detect target cells with low antigen levels. The recipient will employ CRISPR-mediated precise genome editing—inserting DNA cargo into the endogenous TCRA locus to avoid off-target integration and reduce exhaustion—alongside novel HIV envelope-targeting receptors with vastly increased sensitivity to detect infected cells with low levels of antigen.

The multi-principal investigator group will conduct three aims leveraging high-sensitivity engineered T cell receptors, expertise in CD8+ T cell-mediated HIV control, and physiologic assessment tools for engineered T cell killing of infected cells. The project acknowledges that nearly 40 million people live with HIV, a disease without cure, and that rare elite controllers spontaneously suppress HIV through potent HIV-specific CD8+ T cells. To date, no engineered T cell therapy has demonstrated consistent therapeutic efficacy in people with HIV.

Performance occurs in San Francisco, California, with a period of performance from July 9, 2026, through June 30, 2030.

Abstract

The overarching goal of this R01 is to directly channel cutting-edge cell t cell engineering advances in cancer to the context of chronic HIV infection. Nearly 40 million people are living with HIV, a disease for which there is no cure. Rare individuals who spontaneously control HIV ("elite" controllers) have highly potent HIV-specific CD8+ t cells. Engineered t cells have been explored pre-clinically and in several clinical trials to achieve durable HIV suppression and/or potentially elimination of HIV-infected cells from the body. However, to date, none has demonstrated consistent therapeutic efficacy in people with HIV (PWH). Current engineered t cell therapies for HIV have several limitations: random integration events pose risk of malignant transformation; most are not long- lived; traditional chimeric antigen receptors (cars) fail to detect target cells with low antigen; the use of more sensitive t cell receptor (TCR)-t cells is limited by HLA variation and HIV-mediated MHC class i downregulation. We have sought to address these limitations by applying novel t cell engineering approaches such as crispr- mediated precise genome editing (insertion of DNA cargo into the endogenous tcrα [trac] locus) to avoid off- target integration and reduce exhaustion, as well as the design of novel HIV ENV-targeting receptors that have vastly increased sensitivity to detect target cells with low levels of antigen. Building on our collaborative successes, our multi-PI group will leverage our experience with developing advanced approaches to t cell engineering, our expertise in CD8+ t cell-mediated control of HIV, and the innovative tools we have curated to assess engineered t cell killing of infected cells in a more "physiologic" setting to advance three aims. First, using our high-sensitivity engineered t cell receptors, we will perform a high-throughput pooled screen of hundreds of ENV-targeting binders to identify optimal binders and identify qualities of the binders that correlate with functional capacity. Second, we will identify genetic modifications that enhance the functional persistence of HIV-specific engineered t cells in vivo. Finally, we will interrogate the requirements for engineered t cells to eliminate physiologic HIV-infected target cells from people with HIV using innovative, rigorous models. Taken together, we expect that this award will enable the transfer of cutting-edge synthetic biology innovations from immuno-oncology to directly improve engineered t cells for HIV, where we can iteratively test novel and streamline the clinical translation of promising HIV-specific engineered t cell candidates.