# Natural killer cell engineering to target the HIV reservoir

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $798,248

## Abstract

ABSTRACT
HIV continues to be a global health concern that has claimed the lives of millions. Although anti-retroviral therapy
(ART) slows disease progression, ART is not curative due to certain reservoirs of replication-competent virus
that persist during therapy. Therefore, if ART is stopped, then virus can emerge from these reservoirs and rapidly
spread, causing renewed progression towards AIDS. In addition, life-long use of ART is associated with issues
related to cost, medical compliance, and adverse drug events. One strategy for clearing the reservoir of latently
infected cells is to use a kick and kill approach, in which latent cells are “kicked” or activated from latency, and
then concurrently cleared or “killed”. Latency reversal agents (LRA) can “kick” or induce HIV expression from
latent cells, but thus far only a subset of activated latent cells die. Natural killer (NK) cells hold great promise as
killing agents for HIV-infected cells as they re-emerge from latency due to their innate anti-viral recognition and
cytotoxic function. The goal of this research project is to develop new methods to enhance the intrinsic killing
activity of NK cells and to develop NK cell-based kick and kill strategies to reduce the need for life-long ART by
decreasing or eliminating latent viral reservoirs. We intend to approach this proposal by using cutting-edge
technology to engineer the enhanced survival and anti-viral function of NK cells, sophisticated humanized mouse
models of HIV latency, and innovative tools to measure and study the effect of our treatments on the HIV
reservoir. We will test our overall hypothesis that a kick and kill approach will decrease or eliminate the latent
reservoir in the following aims: 1) engineer NK cells to enhance their elimination of HIV-infected cells using an
innovative non-viral mRNA transfection technology, and 2) investigate the effect of novel latency reversal agents
(LRAs) in combination with modified NK cells on HIV reservoirs in a humanized mouse model of HIV latency.
This proposal utilizes Dr. Jerome Zack's (lead PI, UCLA) extensive background in HIV latency and animal
modeling, Dr. Catherine Blish's (dual-PI, Stanford) expertise in NK cell immunobiology and cellular manipulation,
and includes a unique collaboration with Dr. Paul Wender (Stanford), an expert in chemical synthesis, who has
developed a globally unique library of latency reactivating agents (LRAs) with unprecedented latency reversal
capabilities and expanded tolerability that will be tested individually and in synergistic combinations with NK cells.
Together we hope to fully harness the potential of NK cellular therapies, and develop LRA and NK cell
combination therapeutic approaches to provide patients with sustained virologic remissions or complete viral
eradication.

## Key facts

- **NIH application ID:** 10237050
- **Project number:** 1R01AI161803-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Catherine A Blish
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $798,248
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237050

## Citation

> US National Institutes of Health, RePORTER application 10237050, Natural killer cell engineering to target the HIV reservoir (1R01AI161803-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10237050. Licensed CC0.

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