REPLICATION, ESTABLISHMENT OF LATENCY, AND INDUCED REACTIVATION OF HERPES-SIMPLEX VIRUS-GAMMA(1) 34.5 DELETION MUTANTS IN RODENT MODELS

Previous studies have shown that a gene mapping in the inverted repeat s of the L component of herpes simplex virus, type 1 DNA, designated a s gamma(1)34.5, was dispensable for growth in cells in culture but tha t the deletion mutant (R3616) and a mutant containing a stop codon (R4 009) in each copy of the gene were incapable of replicating in the cen tral nervous systems (CNS) of mice. Restoration of the deleted sequenc es restored the wild type virus phenotype. We report here that the gam ma(1)34.5 mutant viruses (R3616 and R4009) replicated in the vaginal t ract of two different strains of mice and guinea pig, although both vi ruses were shed at lower titer and for fewer days than the wild type a nd restored viruses. Both R3616 and R4009 failed to replicate or cause significant pathology in the cornea of Balb/C mice or following intra nasal inoculation of Swiss Webster mice. Analyses of sensory trigemina l and dorsal root ganglia innervating the site of inoculation indicate d that the incidence of establishment of latency or reactivation from latency by R3616 and R4009 viruses was significantly lower than that d etermined for mice infected with wild type or restored virus. Thus, se lective deletion of gamma(1)34.5 gene abolished the capacity of the vi rus to spread from peripheral mucosal sites to the CNS or replicate in the CNS, and diminished the capacity of the virus to replicate at muc osal sites and, subsequently, establish latency, or be able to be reac tivated ex vivo. The results of our studies may have direct implicatio ns for the development of genetically engineered herpes simplex virus vaccines.