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J Virol. 2011 Jul;85(13):6774-83. doi: 10.1128/JVI.02577-10. Epub 2011 Apr 27.

Human herpesvirus 6 suppresses T cell proliferation through induction of cell cycle arrest in infected cells in the G2/M phase.

Author information

1
Department of Microbiology and Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.

Abstract

Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus that primarily infects immune cells and strongly suppresses the proliferation of infected cells. However, the mechanisms responsible for the regulation and suppression mediated by HHV-6 are still unknown. In this study, we examined the ability of HHV-6A to manipulate cell cycle progression in infected cells and explored the potential molecular mechanisms. We demonstrated that infection with HHV-6A imposed a growth-inhibitory effect on HSB-2 cells by inducing cell cycle arrest at the G(2)/M phase. We then showed that the activity of the Cdc2-cyclin B1 complex was significantly decreased in HHV-6A-infected HSB-2 cells. Furthermore, we found that inactivation of Cdc2-cyclin B1 in HHV-6A-infected cells occurred through the inhibitory Tyr15 phosphorylation resulting from elevated Wee1 expression and inactivated Cdc25C. The reduction of Cdc2-cyclin B1 activity in HHV-6-infected cells was also partly due to the increased expression of the cell cycle-regulatory molecule p21 in a p53-dependent manner. In addition, HHV-6A infection activated the DNA damage checkpoint kinases Chk2 and Chk1. Our data suggest that HHV-6A infection induces G(2)/M arrest in infected T cells via various molecular regulatory mechanisms. These results further demonstrate the potential mechanisms involved in immune suppression and modulation mediated by HHV-6 infection, and they provide new insights relevant to the development of novel vaccines and immunotherapeutic approaches.

PMID:
21525341
PMCID:
PMC3126536
DOI:
10.1128/JVI.02577-10
[Indexed for MEDLINE]
Free PMC Article

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