The Products of the Herpes Simplex Virus Type 1 Immediate-Early U S 1/U S 1.5 Genes Downregulate Levels of S-Phase-Specific Cyclins and Facilitate Virus Replication in S-Phase Vero Cells

Abstract

ABSTRACT Herpes simplex virus type 1 ICP22 − /U S 1.5 − mutants initiate viral gene expression in all cells; however, in most cell types, the replication process stalls due to an inability to express γ 2 late proteins. Although the function of ICP22/U S 1.5 has not been established, it has been suggested that these proteins activate, induce, or repress the activity of cellular proteins during infection. In this study, we hypothesized that cell cycle-associated proteins are targets of ICP22/U S 1.5. For this purpose, we first isolated and characterized an ICP22 − /U S 1.5 − mutant virus, 22/n199. Like other ICP22 − /U S 1.5 − mutants, 22/n199 replicates in a cell-type-specific manner and fails to induce efficient γ 2 late gene expression in restrictive cells. Although synchronization of restrictive human embryonic lung cells in each phase of the cell cycle did not overcome the growth restrictions of 22/n199, synchronization of permissive Vero cells in S phase rendered them less able to support 22/n199 plaque formation and replication. Consistent with this finding, expression of cellular S-phase cyclins was altered in an ICP22/U S 1.5-dependent manner specifically when S-phase Vero cells were infected. Collectively, these observations support the notion that ICP22/U S 1.5 deregulates the cell cycle upon infection of S-phase permissive cells by altering expression of key cell cycle regulatory proteins either directly or indirectly.