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 repeats of the L component of herpes simplex virus, type 1 DNA, designated as gamma (1) 34.5, was dispensable for growth in cells in culture but that the deletion mutant (R3616) and a mutant containing a stop codon (R4009) in each copy of the gene were incapable of replicating in the central nervous systems (CNS) of mice. Restoration of the deleted sequences restored the wild type virus phenotype. We report here that the gamma (1) 34.5 mutant viruses (R3616 and R4009) replicated in the vaginal tract of two different strains of mice and guinea pig, although both viruses were shed at lower titer and for fewer days than the wild type and restored viruses. Both R3616 and R4009 failed to replicate or cause significant pathology in the cornea of Balb/C mice or following intranasal inoculation of Swiss Webster mice. Analyses of sensory trigeminal and dorsal root ganglia innervating the site of inoculation indicated that the incidence of establishment of latency or reactivation from latency by R3616 and R4009 viruses was significantly lower than that determined for mice infected with wild type or restored virus. Thus, selective deletion of gamma (1) 34.5 gene abolished the capacity of the virus to spread from peripheral mucosal sites to the CNS or replicate in the CNS, and diminished the capacity of the virus to replicate at mucosal sites and, subsequently, establish latency, or be able to be reactivated ex vivo. The results of our studies may have direct implications for the development of genetically engineered herpes simplex virus vaccines.
Whitley
R J
RJ
Department of Pediatrics, University of Alabama, Birmingham 35294.
Kern
E R
ER
Chatterjee
S
S
Chou
J
J
Roizman
B
B
D000818:Animals; D001483:Base Sequence; D005260:Female; D005727:Ganglia, Spinal / Q000382:microbiology; D005814:Genes, Viral / Q000235:genetics*; D006561:Herpes Simplex / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009296:Nasal Cavity / Q000382:microbiology; D016133:Polymerase Chain Reaction; D018139:Simplexvirus / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D014276:Trigeminal Nerve / Q000382:microbiology; D014621:Vagina / Q000382:microbiology; D014774:Virulence; D014775:Virus Activation / Q000235:genetics*; D014779:Virus Replication; D017201:Virus Shedding