# Enhancing Susceptibility of HIV Reservoirs to CTL Through a Discovery to Translational Approach

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $827,457

## Abstract

PROJECT SUMMARY/ABSTRACT
Although modern antiretroviral (ARV) therapies have dramatically improved the outlooks for people living with
HIV, they are unable to cure infection. For people with HIV a cure would represent freedom from many burdens,
including stigma, expensive medications, and inflammation-associated co-morbidities. A cure would also have
public health benefits, comprising a powerful tool to help end the HIV epidemic. Developing a cure for HIV
requires developing an understanding of how the virus persists for years and decades in people, even when new
rounds of cellular infection (replication) are blocked by ARVs, and despite the ongoing presence of antiviral
immune responses. The dominant paradigm has been that the virus hides in a latent state in infected cells and
is thus invisible to immune responses. Efforts to cure infection have therefore focused on therapeutically
reversing HIV latency to expose these cells to elimination but have thus far yielded disappointing results. This,
along with several converging lines of evidence, have led to more recent hypothesis that hiding from the immune
system may not be the only mechanism by which HIV persists – but rather that these rare populations of infected
cells may have been selected for those that possess cell-intrinsic resistance to killing by cytotoxic T-lymphocytes,
even when they express antigen and are seen. This parallels recent findings from ImmunoOncology where it
has now been well established that some immunogenic tumors undergo selection for cell-intrinsic resistance to
CTL. For this project, we have assembled a team comprising a pioneer in establishing mechanisms of CTL
resistance in tumors, and two HIV experts who have advanced the idea of CTL resistance in this setting through
a series of ex vivo studies. By merging these areas of expertise, we Aim to comprehensively describe
mechanisms of CTL resistance in HIV-infected primary CD4+ T-cells and to discern which of these are at play in
real HIV reservoir cells from people with HIV. We will build from these results to select therapeutic targets and
identify combination approaches that integrate these with HIV-specific CTL and latency reversal strategies to
achieve specific elimination of HIV reservoir-harboring cells ex vivo. We will also leverage an innovative mouse
model to test whether engaging these therapeutic targets limits the seeding of HIV reservoirs in vivo. The results
of this project are thus expected to be: i) laying a broad foundation for understanding CTL resistance in the HIV
reservoir and ii) pre-clinical validation of multiple therapeutic targets with the potential to contribute to a cure for
HIV.

## Key facts

- **NIH application ID:** 10814264
- **Project number:** 5R01AI176601-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** R. Brad Jones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $827,457
- **Award type:** 5
- **Project period:** 2023-03-24 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814264

## Citation

> US National Institutes of Health, RePORTER application 10814264, Enhancing Susceptibility of HIV Reservoirs to CTL Through a Discovery to Translational Approach (5R01AI176601-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10814264. Licensed CC0.

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