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Journal of Virology, April 2006, p. 4005-4016, Vol. 80, No. 8
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.8.4005-4016.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Products of the Herpes Simplex Virus Type 1 Immediate-Early U_S1/U_S1.5 Genes Downregulate Levels of S-Phase-Specific Cyclins and Facilitate Virus Replication in S-Phase Vero Cells

Departments of Medicine and Microbiology and Molecular Genetics, Harvard Medical School at the Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215

Received 22 December 2005/ Accepted 2 February 2006

Herpes simplex virus type 1 ICP22^–/U_S1.5^– mutants initiate viral gene expression in all cells; however, in most cell types, the replication process stalls due to an inability to express ₂ late proteins. Although the function of ICP22/U_S1.5 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_S1.5. For this purpose, we first isolated and characterized an ICP22^–/U_S1.5^– mutant virus, 22/n199. Like other ICP22^–/U_S1.5^– mutants, 22/n199 replicates in a cell-type-specific manner and fails to induce efficient 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_S1.5-dependent manner specifically when S-phase Vero cells were infected. Collectively, these observations support the notion that ICP22/U_S1.5 deregulates the cell cycle upon infection of S-phase permissive cells by altering expression of key cell cycle regulatory proteins either directly or indirectly.

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