# ENHANCEMENT OF CD4CAR T-CELL PERSISTENCE IN VIVO

> **NIH NIH K08** · UNIVERSITY OF WASHINGTON · 2024 · $186,408

## Abstract

PROJECT SUMMARY/ABSTRACT
 HIV is a chronic infection requiring long-term antiretroviral therapy (ART) to halt viral replication and
prevent disease progression. Despite highly effective ART, issues remain with medication access, adherence,
and tolerability. When ART is stopped, the virus rebounds from a reservoir of long-lived infected cells with
resumption of disease progression. Exceptions to this natural disease course are “Elite Controllers” who
spontaneously suppress viral replication by highly functional HIV-specific T-cells. To achieve the robust immune
responses observed in Elite Controllers, we have generated HIV-targeting chimeric antigen receptor (CD4CAR)
T cells that redirect the specificity of T cells to recognize highly conserved regions of HIV. Using our validated
non-human primate (NHP) model of chronic HIV infection, we have shown that CD4CAR T cells induce long-
term viral remission following ART interruption in a subset of NHPs. Our data suggest that long-term CD4CAR
T-cell responses will be essential to advance this therapy broadly for people living with HIV (PLWH).
 We are currently investigating strategies to extend CD4CAR T-cell persistence in vivo. Unlike in cancer,
CAR T cells for HIV must overcome abundant soluble antigen in the form of circulating virus. Our preliminary
data highlight how soluble antigen can inhibit CD4CAR T-cell killing of target cells and promote a dysfunctional
immunophenotype. We hypothesize that soluble antigen must be overcome to achieve comparable success as
observed for cancer. In this proposal, we will thoroughly characterize and overcome the effect of soluble antigen
on CD4CAR T-cell function using our new ex vivo models of viremia to validate next-generation CD4CAR
constructs. We will also extend the persistence of CD4CAR T cells using the immunostimulatory IL15 cytokine,
which can boost HIV-specific endogenous T-cell and cancer-specific CAR T-cell responses. Our preliminary data
confirm the potential for IL15 to enhance the cytotoxicity and survival of CD4CAR T cells. In this proposal, we
will compare a series of IL15-armored CD4CAR T-cell strategies to enhance long-term persistence and durable
cytotoxicity. Finally, we will combine our strategies to generate potent armored CD4CAR T cells with improved
function and persistence during viremia, which we will validate and test in our NHP model of chronic HIV infection.
 Through the mentored research experiences outlined in this K08 proposal, Dr. Bui will develop expertise
in gene therapy and adoptive cellular therapies for the treatment of HIV, which is aligned with his future career
goal to become an independent physician-scientist advancing immunotherapies for infectious diseases. The
hosting institutions have vibrant scientific communities in adoptive cellular therapies and infectious diseases that
Dr. Bui will engage in to foster learning and build collaborations. Dr. Bui will receive comprehensive training in
technical skills, scientific i...

## Key facts

- **NIH application ID:** 10921058
- **Project number:** 1K08AI183990-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** John K Bui
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $186,408
- **Award type:** 1
- **Project period:** 2024-08-05 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10921058

## Citation

> US National Institutes of Health, RePORTER application 10921058, ENHANCEMENT OF CD4CAR T-CELL PERSISTENCE IN VIVO (1K08AI183990-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10921058. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*