# Pathways modulating memory-like properties in NK cells and their impact on HIV control

> **NIH NIH R21** · GEORGE WASHINGTON UNIVERSITY · 2023 · $242,250

## Abstract

Project Summary
Natural Killer (NK) cells are part of the innate immune system and play an important role in controlling HIV
infection. NK cells have been shown to control of SIV replication in the B cell follicles of African Green
Monkeys and in the decrease in acquisition of SHIV in macaques in a vaccination study. Furthermore, studies
presented at CROI2015 and AIDS2018 highlight the importance of NK cells controlling HIV infection in
humans. These studies showed stronger NK responses in post-treatment controllers from the VISCONTI
study. All these previous studies highlight the importance of harnessing NK cells to develop a protective HIV
vaccine or a cure. Recently NK cells have been shown to have ‘adaptive’ or ‘memory-like’ properties. These
properties include a quantitatively and qualitatively increased effector response upon restimulation; enhanced
proliferation in response to low levels of IL-2 or IL-15; enhanced survival in vivo; and enhanced cytolytic
response against different malignancies. In the context of HIV, pre-existing memory-like NK cells have been
shown to control viremia during primary infection. To that end, understanding the signaling pathways and
mechanisms promoting the generation of memory-like NK cells could lead to the development of therapeutic
strategies to enhance HIV control mediated by memory-like NK cells both in the context of vaccine
development and cure interventions. Our preliminary data supports the hypothesis that memory-like NK cells
have an enhanced ability to control HIV infection relative to conventional NK cells. In Aim 1, we will define the
signaling pathways that promote the generation of memory-like NK cells. Specifically, we will investigate the
role of cytokines, antibodies and Toll-like receptor agonists inducing memory-like NK cells. One of the
hallmarks of memory-like NK cells is the epigenetic remodeling of the IFN-γ locus characterized by reduced
DNA methylation and enhanced IFN-γ upon restimulation. As such, we will investigate how DNA methylation
as well as other epigenetic marks such as histone acetylation and histone methylation regulate the generation
of memory-like NK cells. In Aim 2, we will further investigate the ability of memory-like NK cells to control HIV
infection using both in vitro and in vivo models. We will expand our studies to include different viral strains and
evaluate both natural cytotoxicity and antibody-dependent cellular toxicity. The ultimate goal of these research
proposal will be to elucidate signaling pathways that lead to the enhancement of the generation of memory-like
NK cells. If successful, we will provide preclinical data to develop interventions to enhance memory-like NK
effector functions in the context of HIV vaccination and/or cure strategies.

## Key facts

- **NIH application ID:** 10673150
- **Project number:** 5R21AI172042-02
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Alberto Bosque
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $242,250
- **Award type:** 5
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10673150

## Citation

> US National Institutes of Health, RePORTER application 10673150, Pathways modulating memory-like properties in NK cells and their impact on HIV control (5R21AI172042-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10673150. Licensed CC0.

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