Herpes Simplex Virus Gene Products Required for Viral Inhibition of Expression of G1-Phase Functions

Abstract

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.

Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

“…35,36 In control animals, we found Ki-67 labeling indices between 15 and 32%, which are in line with the values previously observed in the biopsy xenograft model, 18 and are somewhat higher than the values reported for human GBM in situ. [37][38][39] In xenograft GBMII, we obtained a remarkable 84% reduction of proliferating cells in plaques after G207 treatment, with 2.5 percent Ki-67 positivity, a figure that resembles grade-II astrocytomas in humans.…”

Varicella-Zoster Virus ORF12 Protein Activates the Phosphatidylinositol 3-Kinase/Akt Pathway To Regulate Cell Cycle Progression

“…The increase in levels of cyclin B1 and cyclin D3 with VZV ORF12 protein was associated with reduced numbers of cells in the G 1 phase and increased numbers of cells in the G 2 /M phase. This differs from HSV infection, in which the virus blocks the progression of cells from the G 1 phase into S phase through the viral proteins ICP0 (47), ICP27 (48), and US1/US1.5 (49). Dysregulation of cell cycle progression by VZV is postulated to be controlled by transcription factors that are regulated by mitogen-activated protein kinases (50).…”

Herpes Simplex Virus Virion Host Shutoff Protein: Immune Evasion Mediated by a Viral RNase?

“…As described below, the multifunctional IE protein ICP27 plays a particularly prominent role in the inhibition of host mRNA biogenesis at both of these levels. ICP27 thus collaborates with vhs to reduce the abundance of host mRNA during infection (15,57). Second, HSV alters the function of the host translational apparatus, such that translation of the residual portion of many of the down-regulated cellular mRNAs is strongly impaired (14,27).…”

“…Genetic studies demonstrate that ICP27 is required for efficient shutoff of host protein synthesis during HSV infection (35,48) and contributes (along with vhs) to the loss of host mRNAs (15,57). These two effects are often equated and ascribed to the splicing inhibition function of ICP27.…”