# Modifying CMV-specificT cells with a novel bicistronic CD4-CAR/maC46 vector to target HIV

> **NIH NIH F30** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $50,520

## Abstract

Project Summary
Human Immunodeficiency Virus-1 (HIV-1) has killed over 35 million people to date and infects 2 million new
people each year. Infection with HIV causes depletion of CD4+ T Cells leading to an immunocompromised
state, and high plasma viral load is correlated with high transmissibility. Antiretroviral therapy (ART), although
effective in controlling plasma viremia and transmission, does not purge the latent or persistent reservoirs
necessary to eliminate infection. Given that non-compliance, socio-economic barriers, and loss to follow up are
common barriers to successful ART therapy, it is imperative to discover therapeutics that provide both lifetime
suppression of viral loads and depletion of viral reservoirs. Recently, studies have demonstrated control of viral
replication and decreasing viral reservoirs in 50% of rhesus vaccinated with a CMV vaccine vector. They
propose that the continuous immunosurveillance of SIV by TEM cells is maintained by the persistent CMV
vectors. To mimic the immunosurveillance and increase the HIV-specific CTL activity in vivo, we will genetically
modify CMV-specific T cells with a chimeric antigen receptor (CAR) and follow the effects on viral reservoirs in
humanized mice and rhesus macaque. The CARs express the CD4 extracellular domain to redirect CTL
activity against HIV, and intracellular T cell signaling domains to stimulate CTL functions. These genetically
modified T cells target a critical step in the viral life cycle independent of MHC presentation, targeting
heterogeneous viruses while avoiding the potential for viral escape. Additionally, based our preliminary studies,
we will include the potent fusion inhibitor maC46 to protect these genetically modified T cells from infection. In
contrast to prior studies, maC46 will be incorporated bicistronically, as opposed to co-transduced. This will
have the added benefit of higher percentages of transduced cells carrying both CD4-CAR and maC46. Such
an innovation would result in greater ability to generate genetically modified T cells when adapted to a clinical
setting. We hypothesize that CMV-specific T cells, when transduced with bicistronic CD4-CAR and fusion
inhibitor, will persist in vivo based on their CMV specificity, but will be protected from infection and will target
residual/reactivated HIV+ cells. These experiments would be the first use of a bicistronic vector incorporating
CD4-CAR with maC46 transduced into CMV-specific T cells, and show rescue of both a humanized mouse,
and rhesus macaque model. We will address this hypothesis through the following specific aims: 1) Transduce
CMV-specific T cells with bicistronic CD4-CAR/maC46 and assess inhibition of viral replication, 2) Adoptively
transfer CMV-specific CD4-CAR/maC46 transduced T cells in vivo using NSG mice and challenge with HIV
infection, and 3) adoptively transfer CMV-specific CD4-CAR/maC46 transduced T cells into SHIV infected
rhesus macaque and compare to the clinical efficacy of...

## Key facts

- **NIH application ID:** 9957012
- **Project number:** 5F30AI150452-03
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Nathan Michel Johnson
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-07-05 → 2022-07-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957012

## Citation

> US National Institutes of Health, RePORTER application 9957012, Modifying CMV-specificT cells with a novel bicistronic CD4-CAR/maC46 vector to target HIV (5F30AI150452-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9957012. Licensed CC0.

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