Selective inhibition of T cell trafficking to brain in acute SHIV.D infected RM will prevent CNS seeding, persistence, and neuropathogenesis

About This Grant

While several studies have characterized myeloid cells as the primary central nervous system (CNS) HIV reservoirs on long-term suppressive antiretroviral therapy (ART), significant knowledge gaps remain in understanding the role of CD4+ T cells in CNS reservoir seeding, viral persistence, and neuropathogenesis. The characterization, and ultimate eradication, of HIV persistence and neuroinflammation remain key goals of HIV research and defining the roles of T cells and their interactions with CNS cell populations driving these processes are essential. In this application, we propose to leverage our validated nonhuman primate model of HIV neuropathogenesis and persistence, our experience defining early CNS seeding, and past studies of T cell sequestration, to determine the impact of blocking T cell circulation during acute SHIV infection on the establishment of durable brain reservoirs. Our model of CNS persistence uses TF SHIV.D.191859 (SHIV.D), a CCR5-tropic virus that efficiently replicates in both CD4+ T cells and macrophages, and consistently infects the CNS, causes neuroinflammation, and persists through ART via long-lived myeloid reservoirs. Genetically barcoded SHIV.D has been validated in persistence experiments, enabling tracking of clonotypes across tissues over time. Our recent studies of barcoded SHIV.D-infected, ART-treated NHP have shown early seeding of the brain that persists through durable ART. Our team has also demonstrated in ART-suppressed SIV-infected rhesus macaques (RMs) that a clinically approved immunomodulating therapy for multiple sclerosis, FTY720, results in rapid and near-complete redistribution of CD4+ T cells from blood into peripheral tissues, with minimal impact on blood monocytes. Thus, FTY720-induced inhibition of T cell, but not monocyte, migration will enable us to dissect the specific role of CD4+ T cells in trafficking of SHIV to the brain and establishing short- and long- term brain reservoirs. RMs will be infected with barcoded SHIV.D and then treated with FTY720 either 1 week prior to infection (Arm 1), or 7 days post-infection (Arm 2), or left untreated (Arm 3). ART will be administered 1- month post-infection, with half of the animals in each arm to undergo necropsy early at 1 month ART, or later at 6 months ART. Arm 4 animals will be infected and receive FTY720 only and be necropsied at study month 2 to compare the effects of FTY720 without ART. In these coordinated NHP studies, we will test our hypothesis that FTY720-mediated inhibition of T cell migration to the brain will prevent early seeding of SHIV brain reservoirs, will limit the size and diversity of the persistent CNS reservoir, and will reduce neuroinflammation on suppressive ART. Using an array of molecular, immunohistochemical, and single cell analyses, we will assess the impact of peripheral CD4+ T cell sequestration on early and late SHIV brain reservoir seeding, then characterize the impacts on neuroinflammation and neurodegeneration. These studies will provide valuable insight into the role of CD4+ T cells in CNS reservoir seeding, including their contribution compared to monocytes, the timing of the reservoir establishment, and their contribution to neuroinflammation.