# Mobilizing host defenses to lymphoid sites of HIV persistence to induce remission

> **NIH NIH R56** · EMORY UNIVERSITY · 2020 · $897,741

## Abstract

Abstract
Distinct cellular reservoirs of replication competent HIV/SIV that are not eliminated by ART are concentrated in
lymph node (LN) B cell follicles (BCF) and T cell zones. Optimizing antiviral activity in lymphoid tissues is of
critical importance for HIV eradication/remission strategies; however, tightly regulated immune cell trafficking
render this challenging. Cytolytic effector T cells are typically excluded from LNs by relative lack of LN and BCF
homing receptors and they fail, once entering, to remain as they move into systemic circulation drawn by a
concentration gradient of sphingosine-1 phosphate (S1P). To counteract these mechanisms, we recently showed
that treatment of ART-suppressed, SIV-infected rhesus macaques (RMs) with the S1P receptor modulator
fingolimod is safe and retains cytolytic immune cells in LN. Furthermore, we showed that administration of
heterodimeric interleukin-15 (hetIL-15) to uninfected and SHIV-infected RMs promotes expansion of cytolytic
CD8+ T cells and NK cells, and promotes their migration to the BCF where infected T follicular helper cells persist.
Fingolimod is FDA approved for multiple sclerosis and hetIL-15 is in clinical trials for cancer and HIV. Our findings
have provided rationale for two upcoming clinical trials in acute HIV infection, testing the safety of fingolimod or
hetIL-15 administration as monotherapies at ART initiation. We propose to move the field forward by exploring
the safety and mechanisms of action of a combined fingolimod and hetIL-15 treatment administered with ART
in acute SIV infection. We hypothesize that these agents will synergize to enhance SIV-specific defenses
in LN, at a time when these defenses are robust; decrease SIV reservoir size; and promote viral remission
after ART interruption. Using the highly relevant model of SIV-infected, ART-treated RMs, we will first determine
the safety, mechanisms of action, and immunological impact of the single and combined FTY720 and hetIL-15
interventions (Aim 1). If our hypothesis is correct, the proposed studies will provide in vivo evidence of the synergy
of FTY720 and hetIL-15 in decreasing virus reservoirs, both in circulation and in lymphoid tissues during ART
(Aim 2), and promoting delayed viral rebound and/or durable control of SIV replication after analytical treatment
interruption (Aim 3).
The proposed studies will be conducted in the most relevant preclinical model of HIV infection; using two
molecules that are either approved by the FDA (fingolimod, for multiple sclerosis) or being tested in clinical trials
(hetIL-15). Our studies are necessary to provide insights into the safety and mechanisms of the combination to
ascertain if such a strategy is safe and plausible for testing in people living with HIV. We believe that the
proposed studies are innovative and higly significant to the HIV cure agenda.

## Key facts

- **NIH application ID:** 10151033
- **Project number:** 1R56AI150401-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** MICHAEL MARCEL LEDERMAN
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $897,741
- **Award type:** 1
- **Project period:** 2020-06-08 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151033

## Citation

> US National Institutes of Health, RePORTER application 10151033, Mobilizing host defenses to lymphoid sites of HIV persistence to induce remission (1R56AI150401-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10151033. Licensed CC0.

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