Human Herpesvirus 6 Suppresses T Cell Proliferation through Induction of Cell Cycle Arrest in Infected Cells in the G ₂ /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 cycleregulatory 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.

Transcriptional Analysis of Host Responses to Marek's Disease Virus Infection in Chicken Thymus

“…Upregulation expression of p21, an important cell cycle arrest factor, was further verified by real-time PCR analysis. The increased expression of p21 in infected cells was also found in other herpesviruses [31,32]. …”

Development of Virus-Specific CD4 + and CD8 + Regulatory T Cells Induced by Human Herpesvirus 6 Infection

“…HHV-6 is an important immunosuppressive and immunomodulatory virus which can induce immunomodulation through a variety of mechanisms, such as lytic infection of CD4 ϩ and/or cytotoxic effector T cells, impairment of antigen-presenting cell functions, induction of inflammatory and immunosuppressive cytokines and/or chemokines, and downmodulation of the CD3/T cell receptor complex (9,10). Our recent studies have demonstrated that HHV-6A infection induced cell cycle G 2 /M arrest in infected T cells via various molecular regulatory processes, further suggesting that this potential mechanism involved in its immune suppression and modulation (11). However, the mechanisms responsible for the regulation and suppression mediated by HHV-6 infection are still under investigation.…”

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

“…Like most herpesviruses, HHV-6 can establish long-term latency in its hosts using immunomodulatory mechanisms to evade the immune system. HHV-6 is indeed known to infect T cells very efficiently and to reduce their proliferation (29)(30)(31), and some viral proteins have been shown to inhibit signaling pathways involved in immune responses (32)(33)(34). However, HHV-6 is also able to promote inflammation by inducing the development of a Th1 phenotype in T cells (35,36), enhancing the cytotoxicity of NK cells (37), and by increasing the production of proinflammatory cytokines and chemokines in different cell types (38,39).…”