Summary auto-generated
This study examined how herpes simplex virus type 2 (HSV-2) affects cell-cycle regulation in African green monkey kidney cells. Researchers infected serum-arrested cells and analyzed cyclin-dependent kinase (CDK) activity and retinoblastoma (Rb) protein phosphorylation. HSV-2 infection induced phosphorylation of Rb and transiently activated CDK2 activity, peaking at 8 hours post-infection before declining. Cyclin A levels increased 2 hours after infection. However, other cell-cycle markers were not activated: CDK4 activity remained unchanged, mitotic CDK (CDC2) activity decreased, and true S-phase progression did not occur despite viral DNA synthesis. CDC2 remained phosphorylated on tyrosine-15, which inactivates its kinase activity. The findings demonstrate that HSV-2 selectively activates specific cell-cycle components, particularly the CDK2-cyclin A complex, without inducing complete cell-cycle progression. The authors propose that partial activation of cell-cycle factors facilitates viral gene expression and DNA replication while preventing cellular mitosis, which may benefit the virus by avoiding cytotoxic T cell targeting of actively cycling cells.
Key findings
- HSV-2 infection transiently activated CDK2 activity (>10-fold increase at 8 hours), while CDK4 and CDC2 kinase activities were not dramatically increased
- Retinoblastoma (Rb) protein was phosphorylated after HSV-2 infection, indicating activation of at least some cell-cycle progression signals
- Cyclin A levels increased early after infection (2 hours), but cyclin B and D-type cyclin levels showed minimal changes
- Despite activation of CDK2, true cell-cycle progression to S-phase did not occur as confirmed by flow cytometry and phosphonoacetic acid blocking experiments
- Viral DNA replication proceeded efficiently independent of complete cell-cycle progression, suggesting HSV-2 selectively activates specific cell-cycle components for viral benefit
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Abstract
Small DNA viruses (adenoviruses, simian virus 40, or human papillomaviruses) induce S-phase progression but prevent cell division to provide precursors for viral DNA replication. Herpes simplex viruses types 1 or 2 (HSV-1 or HSV-2) contain genes which encode DNA- metabolizing enzymes, for example, ribonucleotide reductase, thymidine kinase and dUTPase, suggesting that S-phase factors are not required for an efficient infection. However, several studies indicated that HSV induces some events that occur during cell-cycle progression. To determine if HSV-2 induces S-phase entry, we examined serum-arrested African green monkey kidney cells (CV-1) after infection. Two hours after infection steady-state levels of the S-phase-specific cyclin, cyclin A, increased. S-phase cyclin-dependent kinase activity (CDK2) was stimulated 10-fold 8 h after infection but decreased at 16 or 24 h after infection. Mitotic CDK activity (CDC2) was not activated after infection, in part due to decreases in CDC2 protein levels and inactivation of enzymatic activity resulting from tyrosine phosphorylation of CDC2. Furthermore, CDK4 activity was not dramatically affected by infection. These studies indicate that HSV-2 infection selectively activates CDK2 after infection but cell-cycle progression does not occur. We hypothesize that infection activates certain components of the cell cycle which enhance viral gene expression and DNA replication.