Herpes simplex virus virion host shutoff (vhs) activity alters periocular disease in mice.
During lytic infection, the virion host shutoff (vhs) protein of herpes simplex virus (HSV) mediates the rapid degradation of RNA and shutoff of host protein synthesis. In mice, HSV type 1 (HSV-1) mutants lacking vhs activity are profoundly attenuated. HSV-2 has significantly higher vhs activity than HSV-1, eliciting a faster and more complete shutoff. To examine further the role of vhs activity in pathogenesis, we generated an intertypic recombinant virus (KOSV2) in which the vhs open reading frame of HSV-1 strain KOS was replaced with that of HSV-2 strain 333. KOSV2 and a marker-rescued virus, KOSV2R, were characterized in cell culture and tested in an in vivo mouse eye model of latency and pathogenesis. The RNA degradation kinetics of KOSV2 was identical to that of HSV-2 333, and both showed vhs activity significantly higher than that of KOS. This demonstrated that the fast vhs-mediated degradation phenotype of 333 had been conferred upon KOS. The growth of KOSV2 was comparable to that of KOS, 333, and KOSV2R in cell culture, murine corneas, and trigeminal ganglia and had a reactivation frequency similar to those of KOS and KOSV2R from explanted latently infected trigeminal ganglia. There was, however, significantly reduced blepharitis and viral replication within the periocular skin of KOSV2-infected mice compared to mice infected with either KOS or KOSV2R. Taken together, these data demonstrate that heightened vhs activity, in the context of HSV-1 infection, leads to increased viral clearance from the skin of mice and that the replication of virus in the skin is a determining factor for blepharitis. These data also suggest a role for vhs in modulating host responses to HSV infection.
Smith
T J
TJ
Department of Ophthalmology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Ackland-Berglund
C E
CE
Leib
D A
DA
D000818:Animals; D001762:Blepharitis / Q000473:pathology / Q000821:virology*; D015139:Blotting, Southern; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005260:Female; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D016849:Keratitis, Herpetic / Q000473:pathology / Q000821:virology*; D051379:Mice; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases; D012867:Skin / Q000473:pathology / Q000821:virology; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
D012333:RNA, Messenger; D014764:Viral Proteins; C070722:virion host shutoff protein, Simplexvirus; D012260:Ribonucleases