Deletion of the Herpes simplex 1 internal repeat sequences affects pathogenicity in the mouse.
We have isolated three different herpes simplex virus 1 (HSV-1) recombinant viruses, each frozen in either the P (prototype), IS (inversion of S component), or ILS (inversion of both components) genome arrangement. Common to all three recombinant viruses is the deletion of approximately 14 kilobases (kb) of viral DNA sequences representing greater than 95% of the internal repeat sequences and the insertion of a 9.6 kb mini-Mu genome containing a functional thymidine kinase gene. No unique DNA sequences were deleted from the viral genomes. Analyses of growth curves of the wild-type and recombinant viruses in cell culture has revealed that the recombinants grow somewhat more slowly, producing final titers within 1.5 logs of wild-type HSV-1(F). There is no discernible difference in plaque size or plaque morphology between the recombinant and wild type strains. Analysis of the recombinant viruses in mice reveals the following: I), the recombinant viruses are essentially avirulent, exhibiting drastically increased LD50 values as compared to the wild-type strain by intracerebral injection; ii), the recombinant viruses are not neuroinvasive in that they do not spread from the cornea to sensory ganglion; iii), the recombinant viruses exhibit minimal local replication both in the corneas of infected mice and in the brains of mice inoculated by intracerebral injection; and iv), the recombinant viruses do not establish a reactivable latent infection in the trigeminal ganglion following either intracerebral inoculation or inoculation of scarified corneas. These properties suggest a unique pattern of pathogenesis for HSV mutants in the mouse model.
Jenkins
F J
FJ
Department of Pathology and Infectious Diseases and Microbiology, University of Pittsburgh, and Division of Behavioral Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. jenkins@pcicirs.pci.pitt.edu
Donoghue
A M
AM
Martin
J R
JR
D000818:Animals; D001921:Brain / Q000821:virology; D002522:Chlorocebus aethiops; D003315:Cornea / Q000821:virology; D016679:Genome, Viral; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D011995:Recombination, Genetic / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D017384:Sequence Deletion; D013997:Time Factors; D012668:Trigeminal Ganglion / Q000821:virology; D014709:Vero Cells; D010948:Viral Plaque Assay; D014774:Virulence / Q000235:genetics; D017735:Virus Latency / Q000235:genetics; D014779:Virus Replication / Q000235:genetics