Herpesviruses are a leading cause of human diseases, and nearly 100% of the human population harbors at least one latent herpesvirus. Encephalitis, multiple sclerosis, chronic fatigue syndrome and epilepsy have all been correlated with the presence of human herpesvirus 6 (HHV-6). The HHV-6 family consists of two closely related double stranded DNA beta herpesviruses, HHV-6A and HHV-6B. Our understanding of infection by HHV-6 in the brain has been limited by lack of a genetically tractable small animal model. We have now established that transgenic mice expressing human CD46, a receptor for HHV-6A, are susceptible to HHV-6A infection, and we detect viral DNA up to nine months post infection. Our preliminary studies implicate Toll-like receptor 9 in the host response to infection. Therefore, we hypothesize that HHV-6A will infect specific brain cells and elicit TLR9-dependent cytokines and chemokines. To address this hypothesis we will identify the cellular targets, kinetics of infection in the brain, define the early innate immune responses, and characterize any developing neuropathology. We will also investigate the role of TLR9 in eliciting these responses. The results from the proposed studies will increase our understanding of HHV-6A infection and the resulting immune response in the brain, and provide important information on the broader applicability of this model to the study of HHV-6A neuropathology. Information gained from our studies will help guide development of appropriate therapies to limit or prevent HHV-6-associated neuropathologies.