# Modulating T Cell Activation to Combat HIV Persistence

> **NIH NIH DP2** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $500,000

## Abstract

PROJECT SUMMARY
Major barriers to HIV cure include functional impairment of virus-specific CD8+ T cells and evasion of immune
detection by a reservoir of latently infected CD4+ T cells, both of which persist during antiretroviral therapy (ART).
Critical knowledge gaps in our understanding of the biology regulating both processes limit development of
effective immune therapies to obviate the need for lifelong adherence to ART in persons with HIV (PWH). The
long-term goal is to inform development of such therapies by elucidating molecular mechanisms underpinning
HIV-specific T cell dysfunction and viral persistence. The objective of the proposed research is to identify and
modulate molecular pathways that govern T cell antigen sensitivity in PWH. The rationale is that this information
will guide innovative strategies to combat HIV persistence. Based upon preliminary data identifying a previously
unrecognized T cell activation deficit, distinct from exhaustion, which underlies failure to durably control HIV
infection and an understudied role for monocyte–T cell interactions in altering antigen sensitivity, the central
hypothesis that modulation of T cell activation thresholds will facilitate immune clearance of HIV-infected cells
from persistent viral reservoirs will be examined in three research areas. The first aims to identify and perturb
regulatory mechanisms governing antigen-refractory HIV-specific CD8+ T cells, including their maintenance by
epigenetic control of inhibitory genes and/or cell surface receptors. The second research area aims to define
contributions of HIV-infected antigen-refractory CD4+ T cells to viral persistence, including characterization of
their proviral landscapes and their capacity for latency reversal. The third research area aims to harness
monocyte-mediated modulation of T cell activation thresholds for HIV elimination by defining cell-surface
interactions between monocytes and both CD4+ and CD8+ T cells that modulate antigen sensitivity and then
examining their ability to improve HIV latency reversal and cytolytic viral clearance. The approach is innovative
because it examines novel concepts, establishes new collaborations, and applies high-resolution techniques to
investigate a newly identified dysfunctional T cell state using primary clinical specimens from PWH. The
proposed research is significant because its successful completion will reveal fundamental human T cell
immunobiology that can be exploited to enable the recognition and elimination of persistent HIV reservoirs by
autologous cellular immune responses.

## Key facts

- **NIH application ID:** 10948156
- **Project number:** 1DP2AI184606-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** David Randolph Collins
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $500,000
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948156

## Citation

> US National Institutes of Health, RePORTER application 10948156, Modulating T Cell Activation to Combat HIV Persistence (1DP2AI184606-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10948156. Licensed CC0.

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