# Mechanisms of CTL Resistance in HIV Reservoirs

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $812,001

## Abstract

PROJECT SUMMARY/ABSTRACT
Although modern therapies have dramatically improved the outlooks for people living with HIV, they are unable
to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication.
For any given individual, maintaining lifelong adherence to medication can present substantial challenges.
Moreover, many people do not have access to these expensive medications - in particular those living in
resource-limited settings. It would therefore be of tremendous value to develop novel therapies that can either
cure HIV infection or drive it into remission (a state where levels of virus remain low or undetectable even when
one stops taking ARV medication). One approach to achieving either a cure or remission is to reactivate latent
(hidden) ‘reservoirs’ of virus and harness the immune system to reduce or eliminate these reservoirs. These ‘kick
& kill’ approaches often focus on cytotoxic T-cells (CTL), which are an arm of the immune system specialized in
eliminating virus-infected cells. While the ‘kick & kill’ strategy has shown promise in in vitro models of latency, it
has not yet been effective in clinical trials. In recent work, we have uncovered an additional barrier to eliminating
viral reservoirs by showing that HIV-infected cells are intrinsically resistant to CTL - even when they are forced
to show virus to the immune system by latency reversing agents (LRAs). Although this idea of intrinsic resistance
to CTL has not been widely considered in the context of HIV, it is well known as a factor that limits therapeutic
efficacy in cancer. In this grant application we propose to leverage cutting edge technologies to identify novel
mechanisms by which target cells resist elimination by CTL. These approaches are expected to yield a large
number of ‘hits’, for which we will perform high-resolution mechanistic characterizations. We will then study
samples from people living with HIV to determine which of these mechanisms of resistance play roles in HIV
persistence in vivo. Finally, we will directly test whether therapies targeting this resistance can allow CTL to kill
these ex vivo reservoir-harboring cells. We expect that the outcome of our study will be the identification of novel
targets for the development of therapies aimed at curing HIV infection or enabling remission. More broadly, we
anticipate that the mechanisms identified here will provide fundamental insights into the biology of CTL with
implications for cancer & other conditions.

## Key facts

- **NIH application ID:** 10548335
- **Project number:** 1R01AI170245-01A1
- **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:** 2022
- **Award amount:** $812,001
- **Award type:** 1
- **Project period:** 2022-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10548335

## Citation

> US National Institutes of Health, RePORTER application 10548335, Mechanisms of CTL Resistance in HIV Reservoirs (1R01AI170245-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10548335. Licensed CC0.

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