ABSTRACT Viral infections within the brain pose a unique challenge for the immune system: the host must trigger an effective immune response to control and clear the infection while minimizing neuronal damage. The immunological mechanisms that balance these responses during neurotropic virus infection are not well understood. West Nile virus (WNV) is an emerging neurotropic flavivirus that causes annual epidemics of mosquito-borne encephalitis on a global scale. Following delivery into the skin, WNV replicates in the lymph nodes and spleen followed by entry into the CNS. Here, WNV infects and replicates within neurons, where it is detected by the cytoplasmic RNA helicases RIG-I and MDA5 which, via activation of the mitochondrial antiviral signaling protein (MAVS), lead to the expression of antiviral and proinflammatory proteins, including T cell chemoattractants. The absence of CD8+ T cells leads to uncontrolled virus replication, significant neuronal injury within the brain and loss of protection. To understand how the brain impacts T cell responses during WNV infection, we performed transcriptional profiling on antigen-specific CD8+ T cells isolated from the spleen and brain at early and late times post-WNV infection. We observed that antigen-specific CD8+ T cells infiltrate the CNS around day 7 post- infection (pi), were polyfunctional (IFN-γ, TNF-α) and persist in the brain through day 90 pi. Subpopulations of persistent CD8+ T cells were observed to develop markers consistent with resident memory T cells and maintain persistently elevated levels of type II IFN (IFN-γ). We recently found that CD8+ T cell-derived IFN-γ signaling to microglia, in conjunction with the expression of complement, drives the elimination of presynaptic termini within the hippocampus, which underlies spatial learning defects during recovery from WNV. Further, IFN-γ signaling also promotes astrocyte expression of interleukin (IL)-1, which limits synaptic repair. These findings strongly suggest that the brain microenvironment impacts CD8+ T cell programming that is important for mediating viral control during the acute phase of infection. However, these same antigen-specific CD8+ T cells, through the actions of IFN-γ, contribute to cognitive deficits during the recovery phase. Based on these observations, we hypothesize that during the acute phase of WNV infection, MAVS signaling within neurons and are important for coordinating CD8+ T cell-mediated viral control, neural synapse formation and neurogenesis. However, during the recovery phase, we believe that MAVS signaling within neurons and microglia promote persistence of brain- resident antigen-specific CD8+ T cells that contribute to defects in spatial learning. To address these hypotheses, we seek to determine: 1) the cell-specific contribution of MAVS signaling within the brain during acute WNV infection; and 2) the impact of CD8+ T cell persistence on CNS homeostasis after recovery from viral encephalitis. This st...