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Epitope-engineered HSCs to permit CAR-T cell-mediated CD4-depletion for HIV cure

Award Number: R01AI197956
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/13/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Epitope-engineered HSCs to permit CAR-T cell-mediated CD4-depletion for HIV cure - Project Summary HIV cure has been achieved almost exclusively in individuals undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies using homozygous donors for the CCR5D32 deletion. Although these cases demonstrate that installation of an HIV-refractory immune system is feasible, broader clinical translation is limited by viral rebound from residual reservoir cells, outgrowth of viruses using alternative co-receptors, and the substantial morbidity associated with allogeneic transplantation. These limitations highlight the need for approaches that both protect newly generated immune cells from infection and actively eliminate persistent HIV-infected cells. We propose autologous HSCT-based strategies that integrate precise genome editing with targeted cellular immunotherapy. Using base editors, we introduce functionally silent missense mutations in CD4, the primary HIV entry receptor, to generate immune cells broadly resistant to both CCR5- dependent and CCR5-independent HIV strains while preserving CD4-dependent immune function. In parallel, we engineer additional CD4 variants that render base-edited cells resistant to CD4-specific CAR T cell-mediated depletion, thereby enabling CAR T cells to selectively eliminate residual wild-type CD4+ cells, including those harboring HIV reservoirs, following HSCT. These approaches establish a protected immune compartment while permitting targeted eradication of reservoir cells that drive viral rebound after antiretroviral therapy interruption. We will test the central hypothesis that combining autologous HSCT with CD4-targeted base editing will both prevent infection by HIV variants with distinct co-receptor tropisms and enable CAR T cells to eliminate persistent infected cells, thereby sustaining viral control while preserving immune competence Aim 1: Develop a CD4-modified HSCT approach to prevent HIV infection while preserving CD4+ immune reconstitution. Aim 2: Develop a CD4-modified HSCT approach enabling CAR T cell elimination of residual HIV-infected cells while preserving CD4+ immune reconstitution.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $707,928 )
2026	2026	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	7/13/2026	NEW	$707,928
														Subtotal = $707,928

Grand Total All Awards = $707,928

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Epitope-engineered HSCs to permit CAR-T cell-mediated CD4-depletion for HIV cure

Award Number: R01AI197956

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/13/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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