# Antiviral role of CD8+T cells in ART-treated SIV-infected macaques

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $909,998

## Abstract

PROJECT SUMMARY
HIV infection of humans and SIV/SHIV infection of rhesus macaques (RMs) persist despite long-term ART.
Numerous observations indicate that CD8+ T cells inhibit HIV and SIV replication. More recently, two studies
conducted as part of R01-AI-125064 have shown that: (i) CD8+ lymphocytes are required to maintain virus
suppression under ART (Cartwright, Immunity 2016); and (ii) CD8 depletion reveals a powerful latency-reversal
effect by the interleukin-15 super-agonist N-803 (McBrien, Nature 2020). Collectively, these studies revealed a
previously unrecognized function of CD8+ lymphocytes that, while antiviral in its nature, in the setting of ART
may paradoxically favor the long-term persistence of CD4+ T cells harboring integrated, replication-competent
virus. If further confirmed, this hypothesis would have profound implications in terms of designing HIV “shock
and kill” cure strategies based on modulating the latency promoting activity of CD8+ T cells in combination with
agents that would promote the demise of the CD4+ T cells that have reactivated virus production.
The overarching aim of this proposal is to better understand the ultimate potential of interventions based on the
removal of CD8+ lymphocytes to disrupt SIV/SHIV persistence and reduce or even eliminate the virus reservoir
under ART. We will build upon our previously published data and use the highly relevant, well validated model
of SIV/SHIV infection of rhesus macaques (RM), to answer three important questions: (i) what are the cellular
and anatomic sources of the robust and persistent virus reactivation observed in ART-treated SIV-infected
RMs after combined treatment with CD8α depletion and N-803? (Aim #1); (ii) can we clear the CD4+ T cells
that have reactivated virus production following CD8α or CD8β depletion + N-803 administration in ART-
treated SHIV-infected RMs by treating the animals with a cocktail of Env-specific broadly neutralizing
antibodies (bnAbs)? (Aim #2); and (iii) can we induce apoptosis of the CD4+ T cells that have reactivated virus
production following CD8α depletion + N-803 administration in ART-treated SHIV-infected RMs by treating the
animals with an inhibitor of the anti-apoptotic molecule Bcl-2? (Aim #3).
We are uniquely poised to conduct the proposed experimental work, with an accomplished team of
investigators and key resources at the Yerkes National Primate Research Center of Emory University. We
therefore believe that we will be able to provide novel, critical information on how the latency promoting activity
of CD8+ lymphocytes can be manipulated in vivo to reduce the persistent virus reservoir under ART.

## Key facts

- **NIH application ID:** 10258652
- **Project number:** 2R01AI125064-06
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Guido Silvestri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $909,998
- **Award type:** 2
- **Project period:** 2016-02-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10258652

## Citation

> US National Institutes of Health, RePORTER application 10258652, Antiviral role of CD8+T cells in ART-treated SIV-infected macaques (2R01AI125064-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10258652. Licensed CC0.

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