Pathogenesis of herpes simplex virus type 2 virion host shutoff (vhs) mutants.
During lytic infection, the virion host shutoff (vhs) protein mediates the rapid degradation of mRNA and the shutoff of host protein synthesis. In vivo, herpes simplex virus type 1 (HSV-1) mutants lacking vhs activity are profoundly attenuated. Homologs of vhs exist in all of the neurotropic herpesviruses, and the goal of this study was to determine the virulence of HSV-2 mutants lacking vhs. Two HSV-2 recombinants were used in this study: 333-vhsB, which has a lacZ cassette inserted into the N terminus of vhs, and 333d41, which has a 939-bp deletion in vhs. As expected, both 333-vhsB and 333d41 failed to induce the cellular RNA degradation characteristic of HSV. Corneal, vaginal, and intracerebral routes of infection were used to study pathogenesis. Both viruses grew to significantly lower titers in the corneas, trigeminal ganglia, vaginas, dorsal root ganglia, spinal cords, and brains of mice than wild-type and rescue viruses, with a correspondingly reduced induction of disease. Both viruses, however, reactivated efficiently from explanted trigeminal ganglia, showing that vhs is dispensable for reactivation. The lethality of 333d41 following peripheral infection of mice, however, was significantly higher than that of 333-vhsB, suggesting that some of the attenuation of 333-vhsB may be due to the presence of a lacZ cassette in the vhs locus. Taken together, these data show that vhs represents an important determinant of HSV-2 pathogenesis and have implications for the design of HSV-2 recombinants and vaccines.
Smith
Tracy J
TJ
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA.
Morrison
Lynda A
LA
Leib
David A
DA
D000818:Animals; D002522:Chlorocebus aethiops; D003315:Cornea / Q000821:virology; D005260:Female; D006558:Herpes Genitalis / Q000503:physiopathology* / Q000821:virology; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D016849:Keratitis, Herpetic / Q000503:physiopathology* / Q000821:virology; D051379:Mice; D009154:Mutation; D012260:Ribonucleases; D013116:Spinal Cord / Q000821:virology; D012668:Trigeminal Ganglion / Q000821:virology; D014621:Vagina / Q000821:virology; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
D014764:Viral Proteins; C064566:herpes simplex virus type 2 protein UL41; C070722:virion host shutoff protein, Simplexvirus; D012260:Ribonucleases