# Optimizing the Depletion of innate immune Effector Cells in Nonhuman Primates

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $265,654

## Abstract

PROJECT SUMMARY
Innate immunity plays an important role in the host response against HIV infection. Crucial to this response are
innate immune effector cells including NK cells, monocytes, macrophages and granulocytes, which possess
numerous anti-HIV activities. Notably, monocytes and macrophages may also contribute to HIV persistence
during suppressive therapy by harboring integrated copies of replication-competent HIV proviral DNA. Cytotoxic
NK cells and other Fcγ-RIIIA (CD16) expressing cells can bind to specific antibodies to enable antibody-
dependent cellular cytotoxicity (ADCC), which can mediate killing of HIV-infected cells. However, the
nonredundant role of innate immune effector activity is often difficult to define in vivo. A key barrier is that
modalities to deplete these innate immune cells for loss-of-function studies (e.g., Janus kinase 3 inhibitors, anti-
IL-15 monoclonal antibodies [mAb], anti-MHC-II mAb) can also impact cells of the adaptive immune system,
namely T cells. For example, we previously used anti-IL-15 mAbs to neutralize IL-15 signaling in vivo in rhesus
macaques (RM) to assess the role of NK cells during acute and chronic infection, using the CCR5-tropic
SIVmac239. We observed a massive depletion of NK cells in blood and tissues (DeGotarrdi et al., J. Immunol.
2016), surprisingly minimal impact on SIV replication, and a significant reactivation of oncogenic gammaherpes
viruses (Okoye et al., J. Immunol. 2019). In particular, we noted a reactivation of rhesus RM rhadinovirus (RRV),
a simian γ-herpesvirus closely related to human herpesvirus type 8/Kaposi's sarcoma–associated herpesvirus,
which may have been directly related to the depletion of NK cells, or alternatively due to the impact of IL-15
signaling blockade on other lymphocyte populations such as CD4+ and CD8+ effector memory T cells. Likewise,
use of an anti-CD16 depleting mAb to assess the role of CD16/Fcγ-RIIIA in SIV-infected RM resulted in transient
and often incomplete loss-of-function (Choi et al., J. Virol. 2008). The experiments proposed here will overcome
these limitations by using chimeric antigen receptor (CAR) T cells designed to deplete NKG2A+ and CD16+ cells
in RM. Our preliminary data clearly shows our expertise in this approach using CD20-directed CAR T cells to
deplete B cells in blood and lymphoid tissues of RM. We will use similar techniques to optimize two CAR
molecules, which we have already designed and preliminarily validated. Each is designed to target markers that
are expressed on the vast majority of NK cells in RM (NKG2A) or cells that can mediate ADCC activity (CD16),
which will in turn induce their specific functional deficiency in vivo. CD16 CAR T cells may provide added value
as an approach to deplete myeloid reservoirs. If successful, this project has the potential to substantially advance
the utility of nonhuman primate models to study the specific role of innate immune effector activity in HIV
pathogenesis, vaccine developm...

## Key facts

- **NIH application ID:** 10546827
- **Project number:** 1R21AI172582-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Afamefuna Okoye
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $265,654
- **Award type:** 1
- **Project period:** 2022-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10546827

## Citation

> US National Institutes of Health, RePORTER application 10546827, Optimizing the Depletion of innate immune Effector Cells in Nonhuman Primates (1R21AI172582-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10546827. Licensed CC0.

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