An increasing number of neurological diseases are not known to be caused by persistent viral infection. The current techniques of molecular genetics will be used to analyze the ability of viruses to evade immunologic surveillance, persist, and cause tissue injury. Cytotoxic T lymphocytes (CTLs) are important in clearance of acute viral infection, and their activity is often absent during persistence. We have viral variants which either generate or fail to generate CTLs. Those that generate CTLs cause an acute infection with viral clearance; those that fail to generate CTLs also allow persistence. Our primary goal is to define the structural components of the virus which are important in generating the CTLs and/or allowing the establishment of persistence. The studies proposed here will use laboratory mice infected with lymphocytic choriomeningitis virus (LCMV). Viral genetic variations will be determined by direct RNA sequence analysis, while such factors as host genetics, age and route of infection will be held constant. Persistent variants of acute virus are generated by a single passage and isolation from spleen, and revertants of such variants can be generated by further passage and isolation from brain. Such revertants will be useful in confirming the significance of mutations essential for viral persistence. Once significant mutations have been identified, their affects on viral tropism, replication, and gene expression will be examined. A valuable outcome of these studies would be the identification of molecules peculiar to the nervous system or immune system which are critical in the establishment of the virus. An understanding of those factors which determine whether a viral infection is acute or persistent will lead to strategies for intervention and treatment of viral disease.
