Herpes simplex virus virion host shutoff attenuates establishment of the antiviral state.
Herpes simplex virus mutants lacking the vhs protein are severely attenuated in animal models of pathogenesis and exhibit reduced growth in primary cell culture. As a result of these properties, viruses with vhs deleted have been proposed as live-attenuated vaccines. Despite these findings and their implications for vaccines, the mechanisms by which vhs promotes infection in cell culture and in vivo are not understood. In this study we demonstrate that vhs-deficient viruses replicate to reduced levels in interferon (IFN)-primed cells and that this deficit has both IFN-dependent and IFN-independent components. Furthermore, vhs-defective viruses induce increased and physiologically active levels of IFN, increased amounts of IFN-stimulated transcripts, and more phosphorylated eIF2alpha. In addition, we demonstrate greater accumulation of viral RNAs following infection with a vhs-deficient virus. This leads to the hypothesis that attenuation of viruses lacking vhs may be attributed to increased levels of double-stranded RNA, a potent pathogen-associated molecular pattern. Together these data show that vhs likely functions to reduce innate immune responses and thereby acts as a critical determinant of viral pathogenesis.
Pasieka
Tracy Jo
TJ
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Lu
Betty
B
Crosby
Seth D
SD
Wylie
Kristine M
KM
Morrison
Lynda A
LA
Alexander
Diane E
DE
Menachery
Vineet D
VD
Leib
David A
DA
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D014771:Virion / Q000235:genetics* / Q000378:metabolism*
D015852:Eukaryotic Initiation Factor-2; D016898:Interferon-alpha; D012333:RNA, Messenger; D017471:Receptors, Interferon; D016899:Interferon-beta