Human herpesvirus 6 suppresses T cell proliferation through the induction of infected cell cycle arrest in G2/M phase (154.38)

Abstract Human herpesvirus 6 is an important immunosuppressive and immunomodulatory virus which 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 the 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 G2/M phase. We then showed that the activity of Cdc2-cyclinB1 complex was significantly decreased in HHV-6A infected HSB-2 cells. Furthermore, we found that inactivation of Cdc2-cyclinB1 in infected cells was through the inhibitory Tyr15 phosphorylation resulting from the elevated Wee1 expression and inactivated Cdc25C; Meanwhile, the reduction of Cdc2-cyclinB1 activity in infected cells was also partly due to the increased expression of 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 G2/M arrest in infected T cells via various regulatory mechanisms. These results demonstrate potential mechanisms involved in immune suppression and modulation mediated by HHV-6 infection, and provide new insights relevant to the development of novel vaccines and immunotherapeutic approaches.