# Pathogenesis of Rebound SIV/HIV Viremia after Antiretrovral Therapy

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2020 · $1,527,040

## Abstract

Project Summary
This program project will add to understanding the pathogenesis of SIV/HIV viremia rebound with the long-term
goal of innovating therapeutic strategies enabling sustained remission of HIV infection in a “best-case”
scenario. This scenario involves initiating antiretroviral therapy (ART) soon after infection (“early ART”) and
stopping it after a defined duration - along with short-term use of a new, adjunctive treatment strategy that will
markedly increase the proportion of subjects with sustained remission after stopping early ART. This proposal
will define the cells in mucosal and other tissues that SIV/HIV persistently infects early after infection;
characterize T cell activation-triggered mechanisms hypothesized to both initiate virus production after early
ART stops as well as to cause a cascade of target cell susceptibility and virus infectivity that leads to viremia
rebound; and begin testing mechanism-informed, cell-based interventions to interrupt these “vicious cycles.”
Aims address the following 3 hypotheses about rebound after stopping early ART. 1. Persistent virus
reservoirs are established in mucosal cells soon after infection, and initiate viremia rebound. We will identify
the cell types/subtypes in which SIV initially establishes latency in colon and female reproductive tract mucosa
in the first days after mucosal infection of macaques; determine if those “virus reservoir” cells remain in the
mucosa during suppressive ART in vivo; study virus production from those cells off-ART in cell / tissue models
ex vivo, humanized DRAG mice, and macaques in vivo; and design/perform a pilot observational study of
humans. 2. Temporarily inhibiting mechanistic target of rapamycin (mTOR) will decrease both virus production
from cellular reservoirs and susceptibility of new target cells to infection. We will characterize cellular
mechanisms downstream of mTOR activity that initiate virus production from reservoir cells, and increase
target cell susceptibility to infection, via T cell receptor (TCR) activation, microbial product activation of myeloid
cells, and T cell activation by myeloid cell-derived cytokines. Effects of catalytic mTOR inhibitors will be studied
in macaques in vivo, established ex vivo cellular models of latency/reactivation, as well as new models using
colon mucosal biopsies, excised tonsil tissue, and humanized DRAG mice. 3. Temporarily increasing virion
APOBEC3G (A3G) will decrease virus infectivity. In the ex vivo models and humanized mice, we will test the
hypotheses that T cell reservoirs have low A3G levels before Vif is expressed; that tool compounds (”A3G-
boosters”) will increase A3G levels in Vif-positive virions produced from them; that boosted A3G-mediated
decreased virus spread will add to mTOR inhibitor effects to diminish uninfected target T cell susceptibility to
rebounding infection; and that mTOR inhibition will enhance A3G booster effects on virion A3G content.

## Key facts

- **NIH application ID:** 9964652
- **Project number:** 5P01AI131346-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Richard D'Aquila
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,527,040
- **Award type:** 5
- **Project period:** 2017-07-05 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964652

## Citation

> US National Institutes of Health, RePORTER application 9964652, Pathogenesis of Rebound SIV/HIV Viremia after Antiretrovral Therapy (5P01AI131346-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9964652. Licensed CC0.

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