Targeting CNS reservoirs with CAR/CXCR5 T cells for the long-term remission of HIV

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HIV cure has proven elusive given the persistence of HIV in tissue sanctuaries including the central nervous system (CNS) and lymphoid follicles in people living with HIV (PLWH). Re-emerging data now indicate that myeloid cells in addition to CD4 T cells represent a key population contributing to HIV persistence in tissues and are a major source of viral rebound after antiretroviral therapy (ART) cessation. A better understanding of myeloid reservoirs are needed in order to guide effective cure strategies. Our long-term goals are to 1) understand HIV/SIV reservoirs in myeloid cells in the CNS, and 2) develop a cellular immunotherapy that targets virus-specific chimeric antigen receptor (CAR) T cells to tissue reservoirs of HIV in the CNS and lymphoid tissues to durably suppress HIV replication. Our emerging data suggests that whilst most vRNA+ cells are CD4 T cells during chronic SIV infections, after analytical antiretroviral treatment interruption (ATI), the majority of vRNA+ recrudescing cells may be of myeloid origin in lymphoid tissues. It is unknown what cell types recrudesce HIV post-ATI in the CNS and this will be crucial if we are to have successful remission. In order to achieve sustained HIV remission our group is currently developing a one-time immunotherapeutic for durable remission of HIV in the absence of ART. This treatment is an autologous HIV-specific CAR (specifically CD4-MBL-CAR) T-cell therapy that targets B cell follicles, and may also penetrate the CNS and target cellular viral reservoirs. B cell follicles and the brain are immune protected sites that may permit viral persistence due to low levels of virus-specific CD8 T cells. We will investigate the capacity of CAR-T-cell immunotherapy to clear SIVmac251 in both CD4 T cells and myeloid cells in lymphoid and CNS reservoirs as this will be crucial for an effective HIV cure strategy either alone or in combination with other immuno and non-immunotherapy based approaches in humans. Therefore we hypothesize that myeloid cells in lymphoid and CNS tissue sites represent the predominant cell population responsible for viral recrudescence and using engineered CAR T cells that express CXCR5 will facilitate T-cell egress into both the CNS and lymphoid follicles and lead to durable remission. These pioneering advances will permit the development of animal model systems for cure research that are challenging and impossible to perform in human studies of the CNS for translatability to human clinical studies. Specifically, we propose to 1) To characterize the source of SIVmac251 rebound virus post-antiretroviral therapy treatment interruption (ATI) in the CNS and peripheral tissues, 2) To determine the location, abundance, and persistence of rhesus CAR/CXCR5 T cells in the CNS and their impact on SIVmac251 cellular reservoirs post ART release, and 3) To determine the ability of rhesus CAR/CXCR5 T cells to kill SIV infected myeloid cells in vitro.