# Engineering HIV-resistant CAR T cells for a functional HIV cure

> **NIH NIH R21** · WISTAR INSTITUTE · 2022 · $273,450

## Abstract

Project Summary/Abstract
The human immunodeficiency virus (HIV) promptly subverts the host cellular immune response through rapid
viral escape, as well as high antigen loads leading to chronic immune activation, T cell exhaustion, and immune
dysfunction. The advent of potent antiretroviral therapy (ART) capable of fully suppressing viral replication has
drastically reduced the morbidity and mortality of HIV infection. However, ART must be taken indefinitely as HIV
persists in long-lived stable reservoirs and thus presents a significant public health burden that can only be
alleviated with a preventative vaccine and more potent cure approaches.
Given that HIV effectively evades the cellular immune response, and the latent HIV reservoir is preferentially
seeded with virus harboring relevant cytotoxic T lymphocyte (CTL)-escape mutations, genetic engineering
modalities may offer a potent alternative to intrinsic immunity. Chimeric antigen receptor (CAR) T cells have
shown impressive efficacy in eliminating blood cell cancers in the clinic, and CAR T cells re-engineered to target
HIV using the CD4 ectodomain (CD4-CAR T) represent a potent escape-resistant cellular therapy demonstrated
to have enhanced cytotoxic function over traditional cytotoxic T lymphocytes.
We have recently described the creation of a significantly enhanced dual costimulatory domain CAR T cell
product (Dual CARs), which significantly outperformed 3rd generation CAR T cells in vivo. Importantly, these
studies identified at least two additional hurdles to CD4-CAR T cell efficacy in vivo, which likely informs translation
to the clinic. First, CD4-CAR T cells rapidly upregulate multiple inhibitory receptors, express transcription factors
associated with exhaustion, and display attenuated function ex vivo. Secondly, our studies definitively show that
suppression of plasma viral load requires protection of the CAR T cell product from HIV infection. This proposal
seeks to address these deficits in CD4-ectodomain CAR T cell therapy by 1) defining the mechanism(s) by which
chronic HIV exposure attenuates T cell function, and 2) developing novel combinatorial strategies to fully protect
CD4-CAR T cells from HIV infection, with the ultimate goal of creating a T cell immunotherapy exhibiting
enhanced efficacy in the clinic.

## Key facts

- **NIH application ID:** 10548551
- **Project number:** 1R21AI172616-01
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Daniel Thomas Claiborne
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $273,450
- **Award type:** 1
- **Project period:** 2022-08-19 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10548551

## Citation

> US National Institutes of Health, RePORTER application 10548551, Engineering HIV-resistant CAR T cells for a functional HIV cure (1R21AI172616-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10548551. Licensed CC0.

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