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Implementing novel CRISPR screening models to inform HIV cure strategies by characterizing primary human CD4 T cell resistance to CD8 cytotoxicity

Award Number: F31AI197929
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Implementing novel CRISPR screening models to inform HIV cure strategies by characterizing primary human CD4 T cell resistance to CD8 cytotoxicity - Project Abstract: Signiﬁcant advances in antiretroviral therapy (ART) has enabled functional suppression of HIV, allowing individual individuals on ART to live relatively normal lives. However, viral rebound from a persistent reservoir of provirus-harboring cells following ART cessation demands a lifelong reliance on ART. ART-free control of this persistent reservoir therefore represents the current focus of HIV cure strategies. Recent work from our group and others has identiﬁed HIV-infected CD4 T cells that exhibit cell-intrinsic resistance to CD8 cytotoxicity, despite antigen expression and recognition. While identiﬁcation of resistance factors previously annotated in cancer (such as overexpression of the granzyme inhibitor SERPINB9 and the anti-apoptotic protein BCL-2) has provided some insight concerning underlying mechanisms, the factors leading to this resistance phenotype remain largely unknown. To address this, we have developed a novel genome-wide screening platform that allows identiﬁcation of genes involved in primary human CD4 T cell resistance and susceptibility to CD8 T cell cytotoxicity. In this proposal, we aim to maximize the potential of this newly developed CD4 resistance screening model (CRSM). Additional screens in different contexts will be conducted to further enrich the dataset. We will also employ a methodical pipeline for hit validation and therapeutic characterization. This pipeline will begin with promising hits identiﬁed in the initial screen, including the lipid metabolism-associated PPAR family proteins. This proposal will produce a robust functional genomic dataset thoroughly characterizing the mechanisms underlying CD4 resistance to CD8 killing. With these datasets, we envision the nomination of a range of promising targets for small-molecule sensitization of HIV-infected CD4s to CD8 killing.


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 = $50,114 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	4/1/2026	NEW	$49,538
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	001	1	4/3/2026	NEW	$576
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	002	1	4/3/2026	NEW	$0
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Implementing novel CRISPR screening models to inform HIV cure strategies by characterizing primary human CD4 T cell resistance to CD8 cytotoxicity

Award Number: F31AI197929

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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