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Targeting NKG2A/C+ CD8 T cells for anti-HIV-1 CAR-T therapy

Award Number: R21AI203588
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Targeting NKG2A/C+ CD8 T cells for anti-HIV-1 CAR-T therapy - Abstract/summary A distinguishing feature of reservoir cells in long-term ART suppressed persons with HIV-1 is that they exhibit evidence of selection pressure by innate immune lymphocytes. NKG2A+ NK cells and CD8+ T cells that express NKG2A (deemed innate-like CD8 T cells) are relatively well characterized in blood, where they are cytotoxic and are highly differentiated. Their residence in lymphoid tissues however is less well characterized despite the fact that these anatomic sites are highly enriched for HIV-1 DNA. In healthy uninfected rhesus macaques (RMs), we characterized NKR-expressing lymphocytes in lymph nodes (LNs) and found that in many animals, NKG2A/C+ CD8 T cells comprised nearly half of all NKR-expressing lymphocytes in the LN. These cells exhibited a unique ensemble of qualities that differentiated them from conventional memory CD8 T cells, including (1) a higher capacity to secrete interferon-gamma (2) a lack of canonical exhaustion markers including PD-1 and (3) a stem IL-7R experssing phenotype. Importantly, stem NK2A/C+ CD8 T cells persisted in the LN of SIV+ ART suppressed animals and their frequencies correlated inversely to LN SIV DNA. In these preliminary studies, we were still not able to determine the precise localization of NKG2A/C+ CD8 T cells in the LN. Moreover, it is currently not known whether licensing NKG2A/C+ CD8 T cells to recognize HIV-infected cells could offer superior antiviral efficacy in HIV remission strategies. The main objectives of this proposal are (i) to deﬁne the lymphoid localization of NKG2A/C+ CD8 T cells in the ART suppressed LN and (ii) whether sourcing NKG2A/C+ CD8 T cells for anti-HIV CAR-T therapy would be superior to CAR-T cells sourced from conventional CD8 T cells. Aim 1 will employ multiplex imaging of the LN with Chip Cytometry to determine the LN localization of NKG2A/C+ CD8 T cells. Aim 2 will transduce HIV env-binding CAR vectors under a variety of ex vivo conditions that promote T cell stemness, and in the most optimal condition, generate CAR-T cells from NKG2A/C+ or conventional CD8 T cells and compare their in vitro ability to kill HIV infected cells head-to- head. Finally, aim 3 will infuse large numbers of NKG2A/C+ CAR-T cells into a healthy animal and track their persistence and tissue distribution prior to SHIV infection, expansion capacity and antiviral capacity during acute SHIV infection. Based on our preliminary data, we hypothesize that NKG2A/C+ CAR T cells would mediate superior antiviral activity when compared to convention CD8 T cells. These studies to our knowledge will be the ﬁrst to selectively target NKG2A/C+ CD8 T cells as effectors for HIV remission studies.


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 = $244,988 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	1	8/28/2026	NEW	$244,988
														Subtotal = $244,988

Grand Total All Awards = $244,988

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Targeting NKG2A/C+ CD8 T cells for anti-HIV-1 CAR-T therapy

Award Number: R21AI203588

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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