Biological characterization of a herpes simplex virus intertypic recombinant which is completely and specifically non-neurovirulent

Abstract

In this study, a pre-existing "library" of Herpes Simplex Virus (HSV) intertypic recombinants was found to be not useful for mapping HSV genes controlling viral neurovirulence in mice. Most of these agents were significantly less virulent than either parental type following intracranial inoculation, and in the general case this lessened virulence could be attributed to inefficient replication in any cell type at 38.5 degrees (the normal temperature of the mouse). One agent tested (recombinant RE6) was completely non-neurovirulent following intracranial inoculation of as much as 3.2 X 10(7) PFU. Since about 10 PFU of either 17 Syn+ or HG52 (the "parental" strains of this recombinant) were lethal for mice, RE6 is at least 10 million-fold less neurovirulent than the wild-type strains from which it was produced. The function of the defective gene(s) in RE6 is not yet known, but it is not required for the expression of viral thymidine kinase, efficient replication in cultured cells at 38.5 degrees, or replication in non-neural mouse tissue in vivo. Therefore, the defect in RE6 is in an HSV gene function(s) which is absolutely required for neurovirulence but not for general viral replication. Several possibilities for the molecular nature of the defect in RE6 are discussed.