# Impact of IL-15 immunotherapy on tissue-specific CD8 T cells to reduce the CNS HIV reservoir seeding and persistence

> **NIH NIH R01** · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · 2024 · $975,768

## Abstract

PROJECT SUMMARY
HIV persists long-term in the central nervous system (CNS) even in the presence of antiretroviral therapy (ART).
One strategy to target HIV reservoirs in the CNS is to develop interventions aimed at enhancing the breadth and
magnitude of CD8 T cells, which can penetrate and persist in the brain as tissue resident cells. Our group has
shown that HIV-specific CD8 T cells can limit HIV reservoir seeding in acute infection in the periphery when ART
is initiated during acute infection. We have developed unique tools to analyze these cells in the cerebrospinal
fluid (CSF) and showed that HIV-specific CD8 T cells can also be detected in the CSF during acute HIV infection
and persist in the CSF for up to 2 years after ART initiation. Importantly, the presence of these HIV-specific CD8
T cells is beneficial for limiting neuroinflammation but not enough to fully eliminate HIV reservoirs in the CNS.
The goal of this project is to test whether the immunomodulation of innate-like and adaptive CD8 T cells via a
novel IL-15 super-agonist (N-803) can significantly reduce HIV CNS reservoirs without causing neurotoxicity.
Indeed, IL-15 promotes strong activation and expansion of HIV-specific CD8 T cells and improves their ability to
kill reactivated HIV reservoir cells in vitro. IL-15 enhances memory CD8 T cell generation and persistence in
tissues as well as trafficking to the CNS. IL-15 can also promote the conversion of CD8 T cells into antigen-
independent innate-like effector cells, as well as the activation and expansion of NK cells. In nonhuman primates
(NHP), IL-15 enhanced the function of SIV-specific CD8 T cell responses resulting in reduced plasma viral loads
and increased the migration of SIV-specific CD8 T cells to B cell follicles. These results have supported the
evaluation of IL-15 immunomodulatory potential in HIV remission strategies. However, the potential for IL-15
immunotherapy to reduce HIV persistence in the CNS remains unknown. In this project, we will study the impact
of IL-15 on innate-like and adaptive CD8 T cells in two human HIV remission clinical trials in which participants
receive N-803: the RV550 trial in Bangkok, Thailand, administering 3 doses of N-803 at time of ART initiation
during acute HIV infection, and the ACTG A5386 trial administering 8 doses of N-803 in people with HIV on ART
and undergoing an analytic treatment interruption. We will also conduct two NHP experiments following the
design of the two human trials, that will provide us with access to brain tissue at necropsy. Collectively, these
studies we allow us to determine whether N-803 administration in acute infection is safe for the CNS and can
enhance HIV-specific CD8 T cell-mediated reduction of the CNS reservoirs. We will also determine whether
repeated dosing of N-803 given during ART facilitates innate-like CD8 T cell-mediated reduction of CNS HIV
reservoirs. These results should help define mechanisms by which CD8 T cells can clear HIV reservoi...

## Key facts

- **NIH application ID:** 10891741
- **Project number:** 5R01MH130197-03
- **Recipient organization:** HENRY M. JACKSON FDN FOR THE ADV MIL/MED
- **Principal Investigator:** Lishomwa C Ndhlovu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $975,768
- **Award type:** 5
- **Project period:** 2023-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891741

## Citation

> US National Institutes of Health, RePORTER application 10891741, Impact of IL-15 immunotherapy on tissue-specific CD8 T cells to reduce the CNS HIV reservoir seeding and persistence (5R01MH130197-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10891741. Licensed CC0.

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