# A Universal CAR-NK Cell Targeting Various Epitopes of HIV-1

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2021 · $141,971

## Abstract

PROJECT SUMMARY/ABSTRACT
Engineering T cells and natural killer (NK) cells with anti-HIV chimeric antigen receptors (CAR) has emerged as
a promising strategy to eradicate HIV-infected cells. Current anti-HIV CARs are mostly designed based on
individual broadly neutralizing antibodies (bNAb) recognizing the HIV envelope glycoprotein gp160. However,
they are limited by targeting a single epitope, which cannot counter the enormous diversity and mutability of HIV.
The overall objective of our proposed research is to develop a universal CAR-NK cell platform that can target
various envelope epitopes of different HIV-1 clones. Instead of targeting HIV-1 gp160 directly, we propose to
design a CAR recognizing dinitrophenyl (DNP), a small molecular tag. Our central hypothesis is that anti-DNP
CAR-NK cells can be redirected to target HIV-1 gp160 by using DNP-modified bNAbs as adaptor molecules. In
preliminary studies, we engineer a human NK cell line NK-92 with a CD28/CD3-based anti-DNP CAR. We show
that this CAR-NK cell can recognize and kill gp160-expressing cells, and we also find that the epitope location
on gp160 affects the ability of DNP-modified bNAb to redirect anti-DNP CAR-NK cells against gp160+ cells.
Here, we propose to further test our hypothesis by pursuing two specific aims: 1) Develop and validate an
enhanced universal CAR-NK platform to target HIV-infected cells in vitro; and 2) Determine the anti-HIV efficacy
of universal CAR-NK cells in humanized mouse models. In the first aim, we will develop new anti-DNP CARs
using NK cell-specific signaling domains, such as NKG2D, 2B4, DAP10, and CD16, and we will identify an
optimal CAR-NK construct as well as a panel of DNP-modified bNAbs with the highest potency to activate CAR-
NK cells against HIV-infected cells in vitro. In the second aim, we will examine the ability of the universal CAR-
NK cells, in combination with a cocktail of bNAb-based adaptor molecules, to suppress HIV replication and
reduce viral escape in humanized mice infected with HIV. We will also determine whether the universal CAR-NK
cells can be coupled with latency reversal reagents to reduce or eliminate latent HIV reservoirs. The proposed
research is innovative, in our opinion, because the modular approach is highly flexible and can be used together
with essentially any anti-HIV bNAbs. The proposed research is significant because its successful completion will
lead to the development of a universal CAR-NK cell prototype with significantly expanded epitope coverage,
making it possible to overcome the diversity of HIV-1. This approach, if proved successful, can also be broadly
applied for engineering NK cells, T cells, and hematopoietic stem cells to target HIV and other infectious diseases
as well as cancer.

## Key facts

- **NIH application ID:** 10215523
- **Project number:** 5R21AI155117-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Jianming Xie
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $141,971
- **Award type:** 5
- **Project period:** 2020-07-13 → 2023-01-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215523

## Citation

> US National Institutes of Health, RePORTER application 10215523, A Universal CAR-NK Cell Targeting Various Epitopes of HIV-1 (5R21AI155117-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10215523. Licensed CC0.

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