# Program stem-like CD8 T cells to enhance antiviral immunity against chronic viral infection

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $82,064

## Abstract

PROJECT SUMMARY
 Chronic infection by viruses such as HIV, HBV, and HCV remains a major global health challenge. During
chronic viral infection, CD8 T cells fail to eradicate the virus and develop into a dysfunctional state, termed
exhaustion. Exhausted CD8 T cells, which were first characterized in mouse model of chronic lymphocytic
choriomeningitis virus (LCMV) infection, progressively lose effector function, upregulate inhibitory receptors, and
exhibit dysregulated metabolism. Immunotherapies fail to completely reverse T-cell exhaustion or achieve
sustained viral control during chronic viral infection. Thus, there is an unmet need to develop new strategies to
overcome T-cell exhaustion and enhance the efficacy of immunotherapy against chronic viral infection. Although
exhausted CD8 T cells were initially thought to be a homogeneous population, we and others have recently
shown that a TCF1high antiviral CD8 T cell subset maintains long-term antiviral immunity through self-renewal
and replenishing TCF1low terminally exhausted CD8 T cells during chronic viral infection. Importantly, these stem-
like CD8 T cells are less exhausted and mediate the response induced by various immunotherapies. Our
published studies have demonstrated stem-like CD8 T cells as a separate CD8 lineage with transcriptional and
epigenetic programs that are distinct from those of terminally exhausted CD8 T cells and are tightly regulated by
transcription factors, epigenetic regulators, and cytokines. The goal of this proposal is to define the molecular
and cellular mechanisms regulating the immune response of stem-like CD8 T cells against chronic viral infection
and evaluate strategies to improve antiviral immunity by targeting these pathways. Using chronic LCMV infection
model, cutting-edge metabolic assay, multispectral quantitative imaging, and unique mouse genetic tools, we
will identify the metabolic pathways and cell-cell interactions that endow stem-like CD8 T cells with their superior
antiviral immunity and responsiveness to immunotherapies. These results will lay the foundation for the
development of novel interventions to induce sustained control over chronic viral infections.

## Key facts

- **NIH application ID:** 10923541
- **Project number:** 3R01AI158294-03S1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Tuoqi Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $82,064
- **Award type:** 3
- **Project period:** 2022-08-22 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923541

## Citation

> US National Institutes of Health, RePORTER application 10923541, Program stem-like CD8 T cells to enhance antiviral immunity against chronic viral infection (3R01AI158294-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10923541. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*