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PMID: 9621021 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Requirement for cellular cyclin-dependent kinases in herpes simplex virus replication and transcription.

Journal of virology ·Vol. 72 ·No. 7 ·1998-07-00 ·Pages 5626-37

Schang LM, Phillips J, Schaffer PA

Abstract

Several observations indicate that late-G1/S-phase-specific cellular functions may be required for herpes simplex virus (HSV) replication: (i) certain mutant HSV strains are replication impaired during infection of cells in the G0/G1 but not in the G1/S phase of the cell cycle, (ii) several late-G1/S-phase-specific cellular proteins and functions are induced during infection, and (iii) the activity of a cellular protein essential for expression of viral immediate-early (IE) genes, HCF, is normally required during the late G1/S phase of the cell cycle. To test the hypothesis that late-G1/S-phase-specific cellular functions are necessary for HSV replication, HEL or Vero cells were infected in the presence of the cell cycle inhibitors roscovitine (Rosco) and olomoucine (Olo). Both drugs inhibit cyclin-dependent kinase 1 (cdk-1) and cdk-2 (required for cell cycle progression into the late G1/S phase) and cdk-5 (inactive in cycling cells) but not cdk-4 or cdk-6 (active at early G1). We found that HSV replication was inhibited by Rosco and Olo but not by lovastatin (a cell cycle inhibitor that does not inhibit cdk activity), staurosporine (a broad-spectrum protein serine-threonine kinase inhibitor), PD98059 (an inhibitor specific for erk-1 and -2) or iso-Olo (a structural isomer of Olo that does not inhibit cdk activity). The concentrations of Rosco and Olo required to inhibit cell cycle progression and viral replication in both HEL and Vero cells were similar. Inhibition of viral replication was found not to be mediated by drug-induced cytotoxicity. Efforts to isolate Rosco- or Olo-resistant HSV mutants were unsuccessful, indicating that these drugs do not act by inhibiting a single viral target. Viral DNA replication and accumulation of IE and early viral RNAs were inhibited in the presence of cell cycle-inhibitory concentrations of Rosco or Olo. We therefore conclude that one or more cdks active from late G1 onward or inactive in nonneuronal cells are required for accumulation of HSV transcripts, viral DNA replication, and production of infectious virus.

MeSH Terms
Amino Acid Sequence Animals Cell Cycle/drug effects Chlorocebus aethiops Cyclin-Dependent Kinases/antagonists & inhibitors,physiology DNA Replication/drug effects Kinetin Molecular Sequence Data Purines/pharmacology Roscovitine Simplexvirus/physiology Transcription, Genetic Vero Cells Virus Replication/drug effects
Chemicals
Purines Roscovitine olomoucine Cyclin-Dependent Kinases Kinetin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Schang L M
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6076, USA.
Phillips J
Schaffer P A
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.72.7.5626-5637.1998
Published
1998-07-00
Pages
5626-37
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC110224
Subset
IM
Grants
NINDS NIH HHS · P01 NS035138 · United States
NCI NIH HHS · R01 CA020260 · United States
NINDS NIH HHS · P01NS35138 · United States
NCI NIH HHS · R37CA20260 · United States
External Links
PubMed source DOI: 10.1128/JVI.72.7.5626-5637.1998 PMC Full Text View journal details
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