Herpes simplex virus gene products required for viral inhibition of expression of G1-phase functions.
HSV infection blocks G1 events in the cell cycle and arrests host cell growth in the G1 phase. To further define the mechanism of the effect and determine the viral gene product(s) responsible, we examined various mutant viruses for their effects on cell cycle regulatory proteins (pRb, cyclin D1, and cdk4) and on cell cycle progression into S phase. Unlike the wild-type virus, the ICP27 mutant virus was defective for blocking the phosphorylation of pRb proteins, and the normal pRb pattern was restored in cells infected with a rescued virus. The virion host shutoff (vhs) function, DNA replication, and late gene functions were not required for the virus-induced effects on pRb protein. BrdU incorporation in synchronized HSV-infected cells showed that ICP27 was required for blocking the cell cycle in the G1 phase. Furthermore, ICP27, ICP4, ICP0, and vhs were required for blocking the induction of the G1 cell cycle regulators cyclin D1 and cdk4 in HSV-infected cells. Both ICP27 and the vhs function contributed to the reduction of cyclin D1 mRNA levels in HSV-infected cells: These results provide evidence that HSV-1 ICP27 protein is essential for viral inhibition of G1-phase functions and that certain other HSV proteins are required for some of the viral effects on the cell cycle. Finally, these results show that HSV-1 ICP27 and vhs act jointly to reduce host mRNA levels in infected cells.
Song
B
B
Department of Microbiology & Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Yeh
K C
KC
Liu
J
J
Knipe
D M
DM
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D004261:DNA Replication; D004279:DNA, Viral / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D016193:G1 Phase / Q000502:physiology; D005814:Genes, Viral / Q000502:physiology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D012260:Ribonucleases; D044767:Ubiquitin-Protein Ligases; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C057294:ICP22 protein, human herpesvirus 1; C057120:ICP27 protein, human herpesvirus 1; C045462:ICP8 protein, Simplexvirus; D017874:Immediate-Early Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C048925:herpes simplex virus, type 1 protein ICP4; C070722:virion host shutoff protein, Simplexvirus; D019938:Cyclin D1; C078424:EUS1 protein, Equine herpesvirus 1; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D012260:Ribonucleases