# Harnessing Stem-Like CD8 T Cells for Immunotherapies to Eradicate HIV Reservoirs

> **NIH NIH DP2** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $492,000

## Abstract

Project Abstract
Although combination antiretroviral therapy (cART) effectively suppresses human immunodeficiency virus
(HIV) replication, it does not cure HIV infection and requires costly lifelong treatment. A major challenge for
curing HIV infection is the long-lived latent HIV reservoir, which evades immune recognition and is responsible
for viral rebound shortly after interruption of cART. Substantial research efforts have focused on eliminating
latently infected cells through so-called “shock and kill” strategy, which reactivates latent HIV using latency-
reversing agents (LRAs) to allow for the “kill” by cytolysis or immune-mediated clearance. Particularly, eradication
of theHIV reservoir by anti-HIV T cells, which maintain antiviral immunity in patients as a “living” drug, presents
a promising strategy to either fully resolve the infection or maintain long-term control without cART treatment.
However, clearance of the HIV reservoir by T-cell based immunotherapy remains challenging because of 1) T-
cell exhaustion, 2) the need of lifelong anti-HIV immunity to replace cART, 3) sanctuary sites like B cell follicles
that exclude most HIV-specific CD8 T cells, and 4) unclear impact of LRAs, most of which target epigenetic
pathways, on the function and differentiation of antiviral CD8 T cells in vivo. We and others have recently
characterized a stem-like CD8 T cell subset in chronic lymphocytic choriomeningitis virus (LCMV), simian
immunodeficiency virus (SIV), and HIV infections, as well as in mouse and human tumors. Compared to
terminally exhausted CD8 T cells, stem-like CD8 T cells are less exhausted, mediate long-term immunity, and
respond more potently after treatment of immunotherapies in animals and human. In chronic LCMV, SIV, and
HIV infections, these cells express CXCR5, migrate to B cell follicles and kill infected T follicular helper cells, a
major latent reservoir of HIV and SIV. In addition, frequency of these cells inversely correlates with viremia of
SIV or HIV. Most recently, we showed that the single-cell transcriptomic and epigenetic profiles of stem-like CD8
T cells are distinct from other CD8 subsets generated after acute or chronic LCMV infection. In addition, we
identified a transcriptional program involving transcription factor TOX that is essential for stem-like CD8 T cell
differentiation and the long-term persistence of antiviral CD8 T cells during chronic viral infection. Here, I will
determine the transcriptional and epigenetic programs of stem-like CD8 T cells required for optimal T-cell based
immunotherapy against HIV. I will use animal models of chronic LCMV and SIV infections as well as samples
from HIV patients, and employ cutting-edge technologies, including single-cell profiling of T-cell transcriptomes
and epigenomes, CRISPR/Cas9 screening, and chimeric antigen receptor (CAR) T-cell therapy, to determine
how “shock” by epigenetic modifying LRAs affects the program and antiviral immunity of stem-like CD8 T cel...

## Key facts

- **NIH application ID:** 10447569
- **Project number:** 5DP2AI154450-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Chen Yao
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $492,000
- **Award type:** 5
- **Project period:** 2021-07-08 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447569

## Citation

> US National Institutes of Health, RePORTER application 10447569, Harnessing Stem-Like CD8 T Cells for Immunotherapies to Eradicate HIV Reservoirs (5DP2AI154450-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10447569. Licensed CC0.

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