Nucleotide sequences important in DNA replication are responsible for differences in the capacity of two herpes simplex virus strains to spread from cornea to central nervous system.

Two herpes simplex virus (HSV) intertypic recombinants were isolated with genomes composed entirely of HSV-2(186) nucleotide sequences except for a 6.0 kb segment of HSV-1(17) DNA positioned between 0.40 and 0.44 map units. Following corneal infection of mice, HSV-1(17) and the two intertypic recombinants spread from infected eyes into the central nervous system and induced a fatal encephalitis. Ocular infection with the HSV-2(186) parent did not lead to detectable amounts of virus in the brain, and none of the mice developed encephalitis. The 6.0 kb HSV-1(17) DNA inserted within the genome of the two intertypic recombinants contained nucleotide sequences involved in DNA replication. These include the HSV-1(17) oriL, the HSV-1(17) gene for DNA polymerase and portions of the HSV-1(17) gene coding for DNA-binding protein ICP8. Thus, our results indicate that the difference in the capacity of HSV-1(17) and HSV-2(186) to spread from the cornea into the CNS is determined solely by nucleotide sequences associated with DNA replication.