# Development of Gamma delta CAR-T cells to target CNS HIV reservoir

> **NIH NIH R21** · TULANE UNIVERSITY OF LOUISIANA · 2024 · $222,084

## Abstract

PROJECT SUMMARY
HIV persistence in reservoir tissues remains a major barrier to achieving a therapeutic cure despite effective
antiretroviral therapy (ART). Eradicating HIV-infected cells in the central nervous system (CNS) is particularly
challenging since it is a site of immune privilege and is poorly accessible to ART drugs. While cognitive
impairment among people living with HIV has significantly reduced in the era of modern HIV treatment, about
30% of ART-suppressed HIV patients still display conditions of HIV-associated neurocognitive disorder (HAND),
suggesting that even low levels of HIV persisting in the brain can cause neurological damage. Thus, functional
cure strategies that can safely eradicate replicating virus the CNS reservoir are urgently needed. Emerging
evidence suggests that myeloid cells, including brain macrophages (Mf), are sanctuaries of HIV persistence in
the CNS, and that HIV-infected macrophages are more resistant to CTLs than CD4 T cells. The goal of this
project is to develop a universal gamma delta (γδ) CAR-T platform with dual HIVenv/Mf-targeting for HIV-
infected myeloid cells in the CNS reservoir. Our central hypothesis is that adding Mf specific CAR to anti-HIV γδ
CAR-T cells will enable efficient targeting of HIV-infected cells in the CNS reservoir. Our data in rhesus
macaques show enhanced in vitro killing of HIV-infected monocytic cells by γδ CD4-CAR-T cells and greater
Granzyme B cytotoxicity, which has been shown to be critical for CTL killing of HIV-infected primary
macrophages. Based on the unique functional properties of γδ T cells, including (i) well-documented CTL activity
in immunotherapy of cancer, (ii) ability to migrate to sites of neuroinflammation, and (iii) innate anti-HIV/SIV CTL
functions; we hypothesize that the dual γδ CAR-T cells will induce more effective targeting of myeloid HIV
reservoirs. In Aim 1, we will develop approaches for generating retroviral and lentiviral vector-based γδ CD4-
CAR-T cells toward enhanced targeting of SHIV-infected primary Mf and microglial cells. In Aim 2, we will test
the in vivo potential of the optimized γδ CAR-T cell to migrate and engraft in the CNS during viremic infection
with the novel macrophage-tropic TF SHIV.D model of CNS pathogenesis. The proposed research is significant
because its successful completion will lead to the development of a universal γδ CAR-T cell model with enhanced
targeting of tissue macrophage reservoirs including the CNS in a clinically relevant model of SHIV.D infected
rhesus macaques.

## Key facts

- **NIH application ID:** 10757944
- **Project number:** 5R21MH132483-02
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Namita Rout
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $222,084
- **Award type:** 5
- **Project period:** 2023-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757944

## Citation

> US National Institutes of Health, RePORTER application 10757944, Development of Gamma delta CAR-T cells to target CNS HIV reservoir (5R21MH132483-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10757944. Licensed CC0.

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