The goal of this project is to understand aspects of the pathogenesis of herpes simplex virus (HSV) infection in the nervous system including the mechanism by which this neurotropic virus is regulated within neurons during acute, latent and reactivated infections. A further objective is to understand the relationship between HSV and disease. During FY 1992 studies were continued on the development of transgenic mouse models to investigate the mechanism by which HSV-1 replication is regulated by specific host and viral transcriptional regulatory proteins during nervous system infections. Two new models were developed. Three lines of transgenic mice containing the HSV-1 major immediate early promoter sequence fused to the E. coli beta galactosidase coding sequence were generated. Preliminary experiments in these mice have indicated that, under reactivation conditions and in the absence of viral proteins, host neuronal factors are sufficient to initiate HSV- 1 gene expression. Five lines of transgenic mice containing a deleted form of the HSV- 1 VPl 6 gene which is known to interfere with viral replication in tissue culture have been generated. Experiments which were initiated in FY 1991 and completed in FY 1992 showed that in two lines of transgenic mice expressing the homeodomain protein, Hox 1.3, the pathogenesis of HSV-1 was profoundly altered. Viral spread, replication and mortality were increased in transgenic mice. Thus, for the first time it was shown that a single host protein which is a transcriptional regulator can profoundly alter the pathogenesis of HSV-1.
