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

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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 reservoirs from the CNS as well as CNS safety during an immunomodulatory intervention that may ultimately inform on the development of therapeutic strategies to eradicate the HIV reservoirs from the CNS. 1