# Epigenetic reprogramming of HIV-specific CD8 T cell stemness to enable sustained viral control

> **NIH NIH R56** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $493,016

## Abstract

SUMMARY: Antiretroviral therapy (ART) is the most effective means for reducing mortality and morbidity of
individuals infected with HIV infection, however this therapeutic strategy is costly and is not tolerated well in
many individuals. We are now challenged with the goal of functionally curing individuals that have ART
suppressed HIV. The goal of this proposal is define the DNA methylation programs involved in limiting the
survival and effector function of HIV-specific T cells and to optimize gene editing approaches to develop an
HIV-specific T cell receptor (TCR) T-cell that can provide long-lived control of the virus in chronically infected
individuals. To achieve this goal, we have developed a research program that is focused on understanding the
mechanism for acquisition and maintenance of acquired exhaustion gene expression programs in TCR T cells.
Notably, our group has recently reported that conditional deletion of the DNA methyltransferase 3a (Dnmt3a
cKO) in virus-specific CD8 T-cells prevents functional T-cell exhaustion and preserves a long-lived population
of T-cells that retain a heightened capacity to mount an antiviral response during a chronic viral infection. The
following aims build upon this published work and will facilitate the design of a HIV-specific CAR T cell, as well
as identify epigenetic biomarkers that can be used to assess CAR T cell exhaustion in future clinical trials. The
specific aims of this proposal are:
Aim 1. To determine if DNMT3a-mediated methylation of stemness-associated genes is coupled to the
functional and clonal breadth of HIV-specific CD8 T cells during natural viral control.
Aim 2. To determine if DNMT3a programming is coupled to reduced self-renewal and effector functions
of endogenous and receptor-engineered HIV-specific T cells.
Aim 3. To determine if de novo DNA methylation blockade enhances in vivo TCR T cell mediated HIV
viral control and memory generation.
Completion of the proposed studies will define the epigenetic programs that limit endogenous and engineered
HIV-specific T-cell survival and effector functions, and will advance strategies for generating adoptiveT-cell
therapy that provide durable HIV viral control.

## Key facts

- **NIH application ID:** 10151302
- **Project number:** 2R56AI114442-06
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Benjamin Alan Youngblood
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $493,016
- **Award type:** 2
- **Project period:** 2014-07-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151302

## Citation

> US National Institutes of Health, RePORTER application 10151302, Epigenetic reprogramming of HIV-specific CD8 T cell stemness to enable sustained viral control (2R56AI114442-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10151302. Licensed CC0.

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