# Defining & Characterizing Novel Mechanisms by which HIV-infected Primary CD4+ T-cells Intrinsically Resist Elimination by CTL

> **NIH NIH R56** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $743,679

## 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:** 10236858
- **Project number:** 1R56AI152764-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** R. Brad Jones
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $743,679
- **Award type:** 1
- **Project period:** 2020-09-02 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236858

## Citation

> US National Institutes of Health, RePORTER application 10236858, Defining & Characterizing Novel Mechanisms by which HIV-infected Primary CD4+ T-cells Intrinsically Resist Elimination by CTL (1R56AI152764-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10236858. Licensed CC0.

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