HSV-2 gJ促进病毒细胞-细胞传播的机制及其对HIV-1黏膜共感染的影响研究

HSV-2是造成生殖器溃疡的主要病原，且会增加HIV-1性传播的风险。我们前期发现：HSV-2包膜糖蛋白gJ能促进蛋白表达、合胞体形成以及病毒的细胞-细胞间传播，而且还能增加异源病毒HIV-1和JEV病毒蛋白的表达及病毒产量，但机制不明。结合HSV-2感染形成合胞体并引发上皮层完整性受损的特性以及前期发现的gJ功能，我们推测HSV-2可能通过 gJ在感染中的作用来增加HIV-1的感染率。本项目拟在分子和细胞水平阐明HSV-2 gJ促进蛋白表达、合胞体形成和病毒细胞-细胞间传播的具体机制，利用小鼠模型和人极化的黏膜组织模型研究HSV-2 gJ在黏膜感染中的作用，并在人极化的黏膜组织模型上探究HSV-2 gJ对HIV-1共感染的影响。本项目有助于揭示HSV-2通过细胞-细胞传播逃逸宿主免疫反应的分子机制，并为寻找有效降低HIV-1 性传播的策略提供理论依据。

HSV-2 is the major cause of genital herpes, and can increase the risk of HIV-1 sexual transmission. HSV-2 transmission is predominantly dependent on cell-to-cell contact rather than on particle release and reentry, which represents an efficient strategy for the virus to circumvent the host immune response. However, despite being a predominant mode of HSV-2 spread in vivo, cell-to-cell transmission of the virus has not been studied to the same extent as virus-to-cell transmission. We previously found that HSV-2 gJ promotes protein expression, syncytia formation, and cell-to-cell spread of the virus, which ultimately leads to increased virus production. Furthermore, we found that that gJ enhances viral protein expression and replication of heterologous viruses including HIV-1 and JEV. Given the characteristics of HSV-2 mucosal immune evasion and the potential significance of HSV-2 cell-to-cell spread in mucosal infection, in this proposed project, we intend to elucidate the underlying mechanism by which gJ promotes protein expression, syncytia formation and virus cell-to-cell spread at both molecular and mucosal levels. Using a polarized human cervical explant model, we will further address the impact of HSV-2 gJ on HIV-1 mucosal co-infection. The research outcomes would be important not only for understanding the complexity of HSV-2–host interactions but also for the development of novel strategies to block HSV-2/HIV-1 mucosal infections.