HHV-6通过调控宿主T细胞糖代谢促进病毒复制及免疫逃逸的机制研究

人疱疹病毒6型（HHV-6）是一种免疫抑制病毒，感染宿主细胞后终生潜伏。病毒对细胞代谢的调控是病毒防治研究的新方向和热点。申请者首次发现HHV-6感染诱导宿主T细胞糖代谢增强。据此，本项目提出HHV-6可通过调控宿主T细胞糖代谢促进病毒复制和免疫逃逸的设想。本项目拟进行以下研究：①明确HHV-6对宿主T细胞糖代谢的影响及调控机制，筛选关键的病毒因子及宿主分子；②阐明HHV-6调控宿主T细胞糖代谢对T细胞免疫功能的抑制作用及其逆转策略；③临床水平确定HHV-6感染者T细胞病毒载量、糖代谢水平和T细胞免疫功能状态的关系。④在以上研究基础上，筛选小分子抑制剂及分子靶标，评估其对HHV-6介导T细胞糖代谢改变的逆转作用及抗病毒效果。本项目从代谢角度阐明HHV-6感染复制及免疫逃逸的新机制，研究成果将为HHV-6相关疾病的治疗提供理论及实验基础，也为广谱抗病毒药物的研发开拓新思路。

Human herpesvirus 6 (HHV-6) is an important immunosuppressive virus. Like other herpesviruses, HHV-6 is able to induce latent infection and to persist indefinitely in the host. Understanding how virus infection manipulates cellular metabolism is an emerging and critical field for the effective vaccine development and treatment. In our preliminary study, we have demonstrated that HHV-6 infection dramatically promotes glucose metabolism and glycolysis in infected T cells. Therefore, We speculate that manipulation glucose metabolism of host T cells maybe another strategy used by HHV-6 to escape antivirus immune responses and promote its replication. To confirm this hypothesis, we will carry out the following research: (1) Clarifying the effect and the underlying molecular mechanisms of HHV-6-mediated glucose metabolism in host T cells and screening the key cellular or viral factors responsible for HHV-6-mediated metabolic regulation. (2)Identifying causative link how HHV-6 inhibits T cell functions by HHV-6-mediated metabolic control. (3) Evaluating the correlation of HHV-6 viral load, glucose metabolism and T cell functions by clinical investigations. (4) On the basis of the above studies, small molecule inhibitors and molecular targets will be to screen to evaluate antiviral effect as well as the reversal effect on HHV-6-mediated metabolic control. These results not only identify a novel mechanism of HHV-6 on host cell metabolism and immune escape, but also suggest that targeting the metabolic pathway represents a new avenues for therapeutic development.