The C57BL/6J.YSB consomic males bear a Y chr with a translocation (Yaa) from X bearing TLR7. The translocation reduces susceptibility to EAE, a mouse model of multiple sclerosis. We hypothesized that B6.Yaa mice would also show decreased susceptibility to herpes simplex encephalitis (HSE), another neuroinflammatory condition, compared to the consomic partner, C57BL/6J (B6). Four week-old B6 and B6.Yaa male mice were inoculated with neurovirulent HSV-1. B6.Yaa mice had significantly increased survival (MST = 8 days; 40% survival) compared to B6 (MST = 6 days; 0% survival) by log-rank test. Surprisingly, the brains of the less susceptible B6.Yaa mice had a significantly greater number of viral genome copies than B6 mice (p = 7 x 10-9), as measured by quantitative real-time PCR. We analyzed expression levels of known markers of susceptibility to HSE in the two strains (including cell surface markers, cytokines, and cell-signaling molecules) by real-time PCR assays of RNA from draining lymph nodes and infected tissues. Brains of infected B6.Yaa mice demonstrated significantly increased expression of CD4, IL-1α, IL-1β, IL-6, and TNFα compared to B6 mice on dpi 5. Cluster analysis of expression levels from the 26 transcripts studied (including 21 host transcripts and 5 viral transcripts) in the brains of B6 and B6.Yaa mice demonstrated distinct patterns of gene expression. Thus the Yaa translocation alters the adaptive immune response to HSV-1 and increases survival in these mice.