# Generation of highly differentiated NK cells to act in synergy with broadly neutralizing antibodies to reduce the SIV reservoir and establish viral control in absence of ART

> **NIH NIH R56** · EMORY UNIVERSITY · 2023 · $812,810

## Abstract

PROJECT SUMMARY/ABSTRACT
Lymph nodes and the gastrointestinal tract are major tissue viral reservoirs in people living with HIV and
treated with antiretroviral treatment (ART). A distinguishing feature of SIV infection in African green monkeys
(AGMs), a natural host species for SIV, is the absence of viral dissemination in the lymphoid B-cell follicle
(BCF) and the presence of strong NKcell-mediated control of viral replication in the T-cell zone and BCF of
secondary lymphoid tissues (SLT). In SIVagm-infected AGMs, we recently identified the expansion of NK cells
with a terminally-differentiated phenotype expressing (i) high levels of CD16, an activating Fc receptor that
mediates antibody-dependent cellular cytotoxicity (ADCC), and (ii) low levels of NKG2a, an inhibitory receptor,
that modulates NK cell education via interactions with MHC-E. This terminally-differentiated NK cell (NKTD)
subset (NKG2alowCD16+) exhibited adaptive-like properties and, due at least in part to reduced NKG2a
expression, showed high cytolytic activity against target cells presenting SIV-Env peptides in the context of
MHC-E. The formation of adaptive NKTD cells was blocked in SIVmac-infected rhesus macaques (RMs) in
favor of a subset (NKG2ahiCD16+) with pro-inflammatory function, such as production of IFN, a cytokine also
known for its capacity to increase MHC-E expression on target cells. Remarkably, in a separate cohort of
SIVmac-infected, ART-treated RMs, we demonstrated that AGM-like profiles of adaptive NKTD cells are rescued
via treatment with interleukin-21 (IL-21). In IL-21 treated RMs, the frequency and responsiveness of the
adaptive NKTD cells to target cells presenting SIV peptides in the context of MHC-E strongly correlated with a
reduction of SIV DNA in the gut, lower levels of replication competent virus in SLT, and a delay in viral rebound
following ART interruption. In Aim 1 of this proposal we will define (I) the mechanisms driving the formation
and activity of adaptive NKTD cells, such as cytokine environment and lymphoid inflammation; (II) their tissue
distribution; and (III) ADCC capacity. In addition to NK cells, the impact of IL-21 will be investigated in T-cells
and other immune cells that can respond to IL-21. In Aim 2, we will assess whether and to what extent the
combination of IL-21-induced NKTD cells and a cocktail of anti-SIV broadly neutralizing antibodies (bNAbs)
facilitates, through ADCC-mediated clearance of infected cells, a reduction of viral burden and control of viral
rebound following ART interruption. Specifically, in SIVmac-infected, ART-treated RMs, the “differentiate,
target, and kill” approach will allow differentiation of the NKTD cells with IL-21 followed by targeting of cells
harboring reactivated virus with bNAbs. Using a model reproducing the complex virus-host interactions
occurring in people living with HIV, we expect that the rescue of NK cell terminal differentiation will promote
robust ADCC activity, which will synerg...

## Key facts

- **NIH application ID:** 10883005
- **Project number:** 1R56AI167702-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Mirko Paiardini
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $812,810
- **Award type:** 1
- **Project period:** 2023-08-22 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883005

## Citation

> US National Institutes of Health, RePORTER application 10883005, Generation of highly differentiated NK cells to act in synergy with broadly neutralizing antibodies to reduce the SIV reservoir and establish viral control in absence of ART (1R56AI167702-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10883005. Licensed CC0.

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