title: Human herpesvirus 6 suppresses T cell proliferation through induction of cell cycle arrest in infected cells in the G2/M phase.
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.
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Gu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Chi
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Guangyong
authors.initials: G
authors.lastname: Peng
authors.forename: Fangyi
authors.initials: F
authors.lastname: Xie
authors.forename: Jian
authors.initials: J
authors.lastname: Qing
authors.forename: Dongju
authors.initials: D
authors.lastname: Feng
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Lu
authors.forename: Kun
authors.initials: K
authors.lastname: Yao
mesh_terms: D016203:CDC2 Protein Kinase; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism / Q000494:pharmacology; D018844:Cyclin-Dependent Kinases; D015536:Down-Regulation; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D015654:Herpesvirus 6, Human / Q000472:pathogenicity*; D006801:Humans; D013601:T-Lymphocytes / Q000821:virology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases