# TGFBR1 Blockade as Novel Release and Kill HIV Strategy

> **NIH NIH R56** · NORTHWESTERN UNIVERSITY · 2021 · $786,663

## Abstract

ABSTRACT
For many HIV infected people, lifelong combination antiretroviral therapy (cART) has converted the HIV epidemic
from death sentence into a manageable chronic disease. However, the HIV reservoir persists in all treated
individuals and viral rebound occurs upon cART interruption in the vast majority of patients. Given the challenges
related to lifelong cART treatment such as adherence, viral escape, toxicity, and costs, finding novel ways to
eradicate the virus and/or induce sustained virologic control in absence of cART is a very high priority in the HIV
field. Tissues are major sites for HIV latency and notable contributors to viral rebound after cART interruption.
TGF-β is an important immune suppressor factor, which orchestrates tissue immunity. Levels of TGF-β remain
elevated in HIV infected individuals even after years of fully suppressive cART and contribute to immune
suppression as well as to the development of non-AIDS-related, non-communicable disorders via pro-fibrotic
mechanisms. TGF-β1 inhibits TCR-driven T cell proliferation and the maturation and function of other immune
cell subsets. Importantly, TGF-β is currently being used to induce HIV latency in in vitro models of HIV latency
in primary T cells. Our preliminary data demonstrate that blocking TGF-β signaling in vivo favors HIV latency
reversal especially in tissues. Herein, we propose to test a novel latency reversal and immune stimulatory
strategy based on the activity of a specific inhibitor of the TGF-β type I receptor (TGFBR1) in rhesus macaques.
This strategy has given promising results in a pilot study in macaques and we propose to evaluate the effect of
a prolonged administration similar to the regimen currently employed for cancer therapy. Moreover, we propose
to determine the mechanism of action of the TGFBR1 inhibitor in vivo to better clarify its utility in the development
of novel HIV cure strategies. Finally, we hypothesize that anti-HIV broadly neutralizing antibodies (bNAbs) may
synergize with the TGFBR1 inhibitor in reducing the HIV reservoir and stimulate HIV-specific immune responses.
Thus, we plan to perform a proof-of-concept study to determine the efficacy of combining the TGFBR1 inhibitor
with bNAbs against SIV in SIV infected, cART treated rhesus macaques in reducing SIV reservoir and leading
to virologic control after cART interruption. In summary, we propose the pre-clinical investigation of a novel
TGFBR1 inhibitor that has the potential to be a powerful new addition to the toolbox of “shock and kill” HIV
curative strategies.

## Key facts

- **NIH application ID:** 10358122
- **Project number:** 1R56AI157822-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Elena Martinelli
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $786,663
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358122

## Citation

> US National Institutes of Health, RePORTER application 10358122, TGFBR1 Blockade as Novel Release and Kill HIV Strategy (1R56AI157822-01A1). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10358122. Licensed CC0.

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