# Modeling HIV CAR-T cell trafficking and persistence in Non-Human Primates

> **NIH NIH U19** · UNIVERSITY OF PENNSYLVANIA · 2022 · $740,614

## Abstract

Project 2 - Abstract
Modification of autologous T-cells with chimeric antigen receptor (CAR) molecules has revolutionized the
treatment of many leukemias, and is designed to enable “plug and play” targeting of any surface-expressed
marker of human disease. We are interested in optimizing CAR-T therapies for persistent HIV-1 infection.
Importantly, although the list of hematological malignancies to which CAR-T can be applied is rapidly expanding,
several barriers have prevented application to HIV+ individuals. First and foremost, CAR-T function is frequently
downregulated or lost upon migration to tissues, for example limiting targeting of solid tumors. This also
represents a key limitation for targeting of latently HIV-1 infected cells that reside at sites including lymph nodes,
gut, and the brain. Furthermore, increasing evidence suggests that in order for CAR-T to recognize their cognate
targets, a threshold level of antigen expression may be required at the target cell surface. The central goal of
our U19 consortium is to understand the fate of a CAR T-cell in vivo. In our project, we will compare virus-specific
CARs to CARs directed against CD20+ leukemias, mechanisms of action in antigen-rich vs. antigen-sparse
environments, and the ability of CAR-T to maintain potent, target-specific function after migrating to secondary
tissue sites known to harbor latent virus. We will address these questions in our well-established nonhuman
primate (NHP) model of suppressed HIV-1 infection, focusing on the optimized CD4CAR molecule developed
by Dr. Riley in Project 3. We will first compare CD4CAR-T to a previously-characterized NHP version of the
successful, leukemia-targeting CD20 CAR molecule (“NHP CD20 CAR-T”), in 6 uninfected animals. Next, we
will focus on CD4CAR-T in 12 animals that have been previously infected with simian/human immunodeficiency
virus (SHIV) and suppressed by antiretroviral therapy (ART). Our studies in a total of 18 uninfected or infected,
suppressed animals will provide unprecedented insights into the mechanisms that promote engraftment,
persistence, and function in vivo, and/or lead to silencing or inhibition of antigen-dependent expansion. We have
chosen the NHP model for our studies, as a key aspect of our approach is to better understand CAR-T trafficking
and function in tissues. Using well-established assays to measure tissue resident memory T-cells (TRM), along
with immunohistochemistry and transcriptional profiling approaches, we will characterize CD4CAR-T function in
low and high antigen environments (i.e. before and after release of ART), and ii) benchmark these activities
against our positive control, NHP CD20 CAR-T. Our NHP research aims will apply the gold standard for in vivo
modeling of suppressed HIV infection, and are highly complementary to experiments proposed in Project
1/Wherry, Project 3/Riley, and Project 4/Coughlin and Tebas.

## Key facts

- **NIH application ID:** 10450650
- **Project number:** 5U19AI149680-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** HANS-PETER KIEM
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $740,614
- **Award type:** 5
- **Project period:** 2020-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450650

## Citation

> US National Institutes of Health, RePORTER application 10450650, Modeling HIV CAR-T cell trafficking and persistence in Non-Human Primates (5U19AI149680-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10450650. Licensed CC0.

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