# IL-15 Therapy Combined with TGF-Beta Blockade for Sustained HIV Remission

> **NIH NIH R56** · EMORY UNIVERSITY · 2024 · $927,200

## Abstract

The overall goal of this proposal is to evaluate the safety and therapeutic potential of a novel strategy towards a cure of HIV
infection. The proposed treatment combines soluble IL-15/IL-15Rα with a TGF-β pathway blockade and therapeutic
vaccination to enhance/restore function of anti-viral immunity that will lead to sustained viral remission following anti-
retroviral therapy (ART) interruption against HIV, using the SIV/Rhesus macaque (RM) model. Persistence of viral
reservoirs and dysfunctional anti-HIV immunity represent two major obstacles that must be addressed to achieve sustained
viral remission via blocking viral reactivation in the absence of ART. ART is highly effective in controlling virus replication
but does not significantly improve T cell function and fails to eliminate viral reservoirs. Anti-viral CD8 T cells are critical
for the control of HIV/SIV replication, yet these cells are largely excluded from secondary lymphoid organs which host a
significant population of viral reservoirs during ART, primarily in T follicular helper cells (Tfh) that reside in B cell follicles
and germinal centers (GC). Thus, novel therapies that that not only restore/enhance function of both anti-viral CD8 T cells
and NK cells, but also promote follicular homing of these cells while viral reservoirs are being reactivated will significantly
enhance clearance of infected cells within lymphoid tissues, thereby contributing to sustained viral remission following
analytical ART interruption (ATI). Our preliminary data demonstrate that treatment with the TGF-β pathway inhibitor
galunisertib (GAL) improves anti-retroviral bioavailability in human lymphoid endothelial cells and cytokine (IL-
15/IL15Ra) treatment in vivo markedly enhances the magnitude, proliferation and cytotoxic potential of SIV-specific CD8+
T and NK cells with follicular homing potential, which is critical for the reduction of reemerging viremia post ART
interruption. In addition, in vitro stimulation of chronically infected PBMC with IL-15/IL15R therapy plus GAL treatment
resulted in higher proliferation anti-viral CD8 T cells and NK cells. Importantly, in vivo administration IL-15/IL15Ra plus
GAL treatment in ART treated macaques enhanced antiviral CD8 T cell and NK cell function. Given these highly
encouraging results, we propose to comprehensively test the effects of IL-15/IL-15Ra therapy plus GAL treatment either
alone or in combination on different T and NK cell subsets during chronic SIV infection under the umbrella of ART (Aim
1), and investigate how these changes affect viral reservoirs under ART and viral control after ART interruption (Aim 2).
Last, we will combine the optimal cytokine therapy with vaccination to further enhance the magnitude and breadth of SIV-
specific CD8 T cell responses that we hope will further improve the therapeutic benefit (Aim 3). These studies will advance
our knowledge about how IL-15/IL-15a therapy plus GAL differentially influence the reservoirs an...

## Key facts

- **NIH application ID:** 11118330
- **Project number:** 1R56AI187162-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** ANTHONY T PODANY
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $927,200
- **Award type:** 1
- **Project period:** 2024-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11118330

## Citation

> US National Institutes of Health, RePORTER application 11118330, IL-15 Therapy Combined with TGF-Beta Blockade for Sustained HIV Remission (1R56AI187162-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11118330. Licensed CC0.

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