# Fine Mechanisms of Adaptive NK Cell Formation Against HIV and SIV

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $806,931

## Abstract

The majority of current strategies aiming to prevent, control or eradicate HIV rely on harnessing effector functions
of cytotoxic T cells, helper T cells, B cells and antibodies to attack HIV and HIV-infected cells. However, natural
killer (NK) cells might represent the ideal subset of antiviral effector cells to promptly and potently respond to
HIV exposure. Classically, NK cells are viewed as nonspecific effector cells of the innate immune system that
play critical roles in defense against viral infections, including HIV. Besides their ability to rapidly eliminate virus-
infected cells without the need for prior antigen sensitization, several independent studies from the past 12 years
have demonstrated that subsets of murine, non-human primate (NHP) and human NK cells are capable of
adaptive immune functions, including antigen-specificity and recall responses. Our laboratories provided the first
clear evidence of antigen-specific NK cell memory in a primate species, elicited by HIV/SIV infection and
vaccination. Preliminary data presented in this application now show that antigen-specific NK cell memory with
potent antiviral functions develops upon exposure to HIV in humans and provide the first mechanistic evidence
for antigen-specific NK cell memory, strongly supporting a role for HLA-E and its activating ligand NKG2C in
antigen-specific NK cell responses. Collectively, these findings suggest that antiviral functions of adaptive NK
cells have tremendous potential to be exploited for vaccine design, curative or other therapeutic interventions
against HIV. However, the most significant obstacles to harnessing adaptive NK cell functions is the opacity
surrounding the mechanisms of their formation and their potential to mediate protection in primate species. In
this study, we propose to address the overarching hypothesis that adaptive NK cell responses develop
kinetically to inhibit SIV/HIV replication and use disparate mechanisms of MHC recognition and
alternative epigenetic and metabolic programs through two focused yet independent Aims: (i) Define in vitro
and in vivo mechanisms of MHC-E-restricted NK cell antigen specificity against HIV and SIV infections;
and (ii) Delineate NK cell-specific molecular programs influencing adaptive NK cell formation against
HIV and SIV. Taken together, these investigations will provide critical information on the development of antigen-
specific memory NK cells against SIV/HIV and determine the capacity of this NK cell subset to control viral
replication. If successful, these studies will identify clear pathways that could be exploited to further enhance
adaptive NK cell antiviral activity in future HIV vaccine and/or cure strategies.

## Key facts

- **NIH application ID:** 10893985
- **Project number:** 5R01AI161010-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Stephanie Jost
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $806,931
- **Award type:** 5
- **Project period:** 2021-08-20 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893985

## Citation

> US National Institutes of Health, RePORTER application 10893985, Fine Mechanisms of Adaptive NK Cell Formation Against HIV and SIV (5R01AI161010-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10893985. Licensed CC0.

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