# Harnessing adaptive NK cell transfer to deplete viral reservoirs

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $760,984

## Abstract

PROJECT SUMMARY
Natural killer (NK) cells provide an immediate defense against viruses and tumors by virtue of their ability to
respond to infected or malignant cells without prior antigenic stimulation. This is accomplished through the
integration of signals from activating and inhibitory NK cell receptors (aNKRs & iNKRs). In humans and other
primate species, these include C-type lectin receptors, such as CD94/NKG2A and CD94/NKG2C, and the
highly polymorphic killer-cell immunoglobulin-like receptors (KIRs), both of which interact with MHC class I
ligands. These receptor-ligand interactions are fundamental to the ability of NK cells to differentiate healthy
cells from unhealthy cells and provide a potential mechanism of specificity for the development of “NK cell
memory”. NK cells can have a significant impact on HIV-1 infection. KIR and HLA class I polymorphisms have
been identified that are associated with lower viral loads and slower courses of disease progression and
certain NK cell subsets can kill HIV-infected cells in culture. Thus, NK cell-based therapies represent a
promising approach for targeting HIV-infected cells and reducing the size of viral reservoirs. We hypothesize
that viral peptides bound by the MHC class I ligands of aNKRs are critical to NK cell recognition and killing of
HIV/SIV-infected cells and that the adoptive transfer of ex vivo activated NK cells in combination with latency
reversal can deplete viral reservoirs in SIV-infected macaques on suppressive antiretroviral therapy (ART).
In Aim 1, we will determine the contribution of viral peptides bound by MHC class I ligands of aNKRs to NK
cell recognition of HIV- and SIV-infected cells. These studies will utilize high-throughput cellular assays to
rapidly screen viral peptides for MHC class I interactions with aNKRs and to identify substitutions that disrupt
these interactions. The corresponding changes will be introduced into HIV-1 and SIV to assess their impact on
NK cell responses to virus-infected cells. In Aim 2, we will assess the capacity of ex vivo expanded NK cells in
combination with latency reversal to deplete viral reservoirs in SIV-infected, ART-suppressed rhesus
macaques. This aim will take advantage of barcoded SIV and a potent new latency reversal agent to compare
with maximal sensitivity the ability of autologous versus allogeneic NK cell transfer to reduce the rate of viral
reactivation after discontinuing ART. In Aim 3, we will test the hypothesis that the depletion of viral reservoirs
by adaptive NK cell transfer can be enhanced by an Env-specific antibody with antibody-dependent cellular
cytotoxicity against SIV-infected cells. This aim will use a similar approach as Aim 2 to determine the extent to
which coupling NK cell effector function to the unparalleled specificity of antibodies can maximize reservoir
depletion. These unprecedented studies will provide a better understanding of the role of viral peptides in NK
cell recognition of HIV- and SIV-i...

## Key facts

- **NIH application ID:** 10809780
- **Project number:** 5R01AI161816-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Edward Barker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $760,984
- **Award type:** 5
- **Project period:** 2021-04-16 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809780

## Citation

> US National Institutes of Health, RePORTER application 10809780, Harnessing adaptive NK cell transfer to deplete viral reservoirs (5R01AI161816-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10809780. Licensed CC0.

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