# Understanding and Reversing T Cell Dysfunction to Control and Eliminate Persistent HIV Reservoirs

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $420,000

## Abstract

PROJECT SUMMARY
Antiviral cytotoxic CD8+ T lymphocytes (CTLs) are critical for controlling viremia and are central to HIV
cure/remission strategies. However, there is a fundamental gap in understanding the molecular determinants
underlying the onset and persistence of HIV-specific CTL dysfunction in individuals who fail to control viremia,
preventing strategies to restore CTL function for HIV prevention and durable remission. The objective of this
application is to define molecular regulation and biomarkers of HIV-specific CTL dysfunction. Based upon strong
preliminary evidence, we hypothesize that initiation of CTL dysfunction preceding loss of virologic control and
maintenance of CTL dysfunction during antiretroviral therapy are mediated by cell-intrinsic mechanisms,
identification of which will inform therapeutic interventions to combat HIV persistence. We will define regulatory
mechanisms of CTL dysfunction using an integrative, multi-omics systems biology approach at intra-patient,
antigen-specific, and single-cell resolution, and validate using gene editing for restoration of antiviral CTL
function. The rationale of the proposed studies is that a more precise understanding of the molecular
mechanisms governing durable versus failed CTL-mediated HIV control will be needed to advance CTL-based
HIV cure strategies. Aim 1 will define mechanisms by which CTL dysfunction is initiated preceding breakthrough
viremia in HIV controllers. Preliminary data demonstrate that a progressive loss of antiviral CTL function
precedes viral rebound in patients who lose HIV control. Experiments in this aim will elucidate regulatory
pathways governing the initiation of CTL dysfunction by evaluating changes in epigenetic, transcriptional, and
post-transcriptional signatures using longitudinal specimens preceding loss of HIV control. Regulatory pathways
will be disrupted using gene editing for mechanistic validation. Aim 2 will define mechanisms by which CTL
dysfunction is maintained during pharmacologic HIV suppression and the extent to which function can be
restored. Preliminary evidence indicates that CTL dysfunction is not restored by antiretroviral therapy or immune
checkpoint blockade. Experiments in this aim will identify molecular mechanisms by which dysfunction is
maintained in non-escaped HIV-specific CTLs during antiretroviral therapy using a multi-omics approach, and
determine the extent to which CTL function can be restored by inhibition and gene editing of identified regulatory
networks. This approach is innovative because it couples controlled intra-patient comparisons of epitope-specific
CTLs by population and single-cell transcriptional, post-transcriptional, and epigenetic profiling with gene editing
in primary cells to interrogate the molecular mechanisms that underlie HIV-specific CTL dysfunction. The
proposed research is significant because it will provide the mechanistic groundwork for development and
evaluation of interventions that aim to ha...

## Key facts

- **NIH application ID:** 10308059
- **Project number:** 5R01AI149704-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Bruce D Walker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $420,000
- **Award type:** 5
- **Project period:** 2019-12-23 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308059

## Citation

> US National Institutes of Health, RePORTER application 10308059, Understanding and Reversing T Cell Dysfunction to Control and Eliminate Persistent HIV Reservoirs (5R01AI149704-03). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10308059. Licensed CC0.

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