# How antigen exposure shapes the subsequent NK cell response to HIV

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $863,699

## Abstract

The goal of this proposal is to determine how antigen exposure shapes subsequent Natural Killer cell
responses to HIV. We propose to identify NK functional subsets in naïve and antigen-primed human NK cells
using single-cell sequencing and multi-parametric flow cytometry. We propose to verify the relevance of
such functional subsets to NK cell-mediated host protection from HIV disease using our established in vitro
and in vivo functional assays. NK cells are innate lymphocytes that live up to their name by their ability to kill
infected or tumor cells within minutes of exposure. However, the targeting of NK cell effector functions has not
been a significant focus in vaccine development, which has mainly focused on their T and B cell counterparts
in the adaptive immune system. Recent findings from the PI of this application indicate that NK cells deserve
more attention. We recently published exciting new data that human NK cells remember prior antigen-
encounters and mediate enhanced recall responses to HIV-Envelope in humanized mice. Here, we present
unpublished new data that HIV-Env-primed memory NK cells suppress HIV viral titers upon experimental viral
challenge. These findings have opened the opportunity to harness NK memory functions for vaccine design.
However, high NK cell receptor repertoire diversity is associated with an increased risk of HIV acquisition,
and NK cell receptor repertoires diversify throughout life, presumably in response to antigen exposure.
These data present a challenge for vaccine design, as both protective NK memory responses and potentially
risky NK repertoire diversifications are consequences of antigen exposure. The identification of specific
functional subsets of HIV-responsive, host-protective NK cells and their mechanisms of host protection is
therefore critically needed. Their discovery will open the door for revised vaccine designs that endure the
incorporation of NK memory, rather than harmful receptor repertoire diversity, as a host protective outcome.
Our data will enable the pre-screening of vaccines for the induction of protective NK functional subsets in pre-
clinical models and allow for improved vaccine efficacy evaluations in humans. Thereby, our studies will
provide the rationale to develop novel vaccines that exploit the antiviral activity of NK cells to protect humans
from HIV infection while avoiding harmful activity.

## Key facts

- **NIH application ID:** 10374918
- **Project number:** 5R01AI161014-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Silke Paust
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $863,699
- **Award type:** 5
- **Project period:** 2021-03-18 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374918

## Citation

> US National Institutes of Health, RePORTER application 10374918, How antigen exposure shapes the subsequent NK cell response to HIV (5R01AI161014-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10374918. Licensed CC0.

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