Despite suppressive antiretroviral therapy in HIV infected human beings that maintains their immunocompetence, brain dysfunction develops and impairs their quality of life. To investigate HIV residence, disease, and recovery in the central nervous system (CNS) we have studied the infection of conventional mice by EcoHIV, a chimeric HIV with tropism switched from human to rodent. Infected mice reliably develop neurocognitive impairment (NCI). We found that innate immune responses to Toll-like receptor ligand polyinosinic-polycytidylic acid (poly I:C) reduce virus burden and restore cognitive function in mice chronically infected by EcoHIV. Remarkably, poly I:C also induces a long-lived response that largely prevents EcoHIV infection and NCI. Here, we shall exploit these successful treatments to achieve functional EcoHIV cure in the murine CNS as a complement to existing antiretroviral therapies. The Specific Aims are 1) to exploit reversal of HIV NCI through intermittent poly I:C treatment of chronically infected mice to identify the changes in gene expression underlying both the essential antiviral responses and the critical neuronal genes restored to normal function. Of particular interest is the identification of specific cell types mediating protective immunity and their specific products, since all brain cell types can respond to poly I:C. 2) to investigate reversal of HIV NCI through long-lived poly I:C responses by chronically infected mice. Poly I:C induces both immediate and long-lived antiviral programs that prevent EcoHIV infection and the development of HIV NCI. Our overall goal in this application is to bring genomics and imaging techniques to expose the routes of HIV NCI as well as the antiviral routes that restore function. Here, we will test whether chronically infected mice can mount a long-lived poly I:C response that restores normal cognitive function. It will be critical to compare the gene expression programs initiated by intermittent poly I:C treatment, likely Type I interferon, to those comprising the long-lived poly I:C response that may include the canonical innate immune training program. To monitor EcoHIV infection and disease in the brain we shall employ QPCR to measure virus burden and radial arm water maze (RAWM) to detect cognitive defects, brain RNA-seq to reveal cellular gene dysregulation, RNAscope to assign brain infection to cell types, and confocal microscopy to determine cell types mounting protective innate responses. Since innate immunity is not pathogen specific, this exploratory program may reveal approaches to induce innate responses that protect against other viruses invading the brain.