# Turning off HIV White Noise: Switching from Long-Lived to Short-Lived Reservoir

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $1,145,669

## Abstract

HIV persists in all treated individuals and in most cases viral rebound occurs promptly upon antiretroviral
treatment interruption (ATI). Tissues are major sites of HIV persistence during cART and, notably, the
gastrointestinal tract is the first site were rebound is detectable via SIV-end ImmunoPET/CT in a live SIV
infected animal upon ATI. However, a lot is still unknown about the mechanisms of viral persistence in tissues.
This is mostly because of logistical barriers in sampling deep tissues and the focal nature of HIV/SIV infection.
Our team has developed a sampling workflow based on ImmunoPET/CT signal that overcomes these
difficulties and allows sampling of areas of “rebound-competent reservoir” in tissues in a live animal. 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-β 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 with primary T cells. Our
preliminary data demonstrate that blocking TGF-β signaling in vivo favors HIV latency reversal especially in
tissues. Moreover, we found that TGF-β blockade stimulates SIV-specific immune responses and decreases
BCL-2 expression in memory T cells both in vivo and in vitro. These exciting new data support a view of TGF-β
as a critical factor in maintaining immune cells into a resting state mostly resistant to apoptosis. Hence, we
hypothesize that blocking TGF-β will not only increase the frequency of latency reversal events, but also
enhance the elimination of the viral reservoir by increasing its susceptibility to immune and viral-mediated cell
death. We will test this hypothesis by focusing on 3 specific aims. Aim 1 will be an investigation of the
mechanisms of TGF-β blockade in vivo. We will leverage PET/CT-guided sampling to obtain tissue areas
where virus reverses following TGF-β blockade and analyze the cells in these tissues for their transcriptomic
profiles in their own microenviroment. In Aim 2, we will dissect the mechanisms of TGF-β blockade ex vivo to
understand the pathways dependence of the effect of TGF-β blockade on HIV latency and on the survival
program of central memory T cells. Finally, in Aim 3, we will dissect the combination of TGF-β blockade and
PD-1 blockade on the differentiation program and apoptosis sensitivity of the cells harboring the viral reservoir
in vivo. In conclusion, we designed a comprehensive strategy that will help us understanding the potential of
this novel strategy to bring us closer to an HIV cure.

## Key facts

- **NIH application ID:** 10676478
- **Project number:** 1R01AI176599-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Elena Martinelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,145,669
- **Award type:** 1
- **Project period:** 2023-03-22 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10676478

## Citation

> US National Institutes of Health, RePORTER application 10676478, Turning off HIV White Noise: Switching from Long-Lived to Short-Lived Reservoir (1R01AI176599-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10676478. Licensed CC0.

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