HSV-2极早期蛋白ICP27抑制IFN-β产生的机制及其对HIV-1黏膜共感染的影响研究

HSV-2是生殖器疱疹的主要病原体，且增加HIV-1性传播的风险，可通过逃逸宿主免疫建立潜伏感染。我们前期发现：有复制能力的HSV-2在黏膜水平有效抑制IFN-β的产生；HSV-2极早期蛋白ICP22通过阻碍IRF3通路抑制IFN-β的产生，但ICP22缺失病毒并未完全丧失抑制IFN-β产生的能力；而另一个HSV-2极早期蛋白ICP27可以在细胞水平显著抑制IFN-β的产生，但机制不清楚。本项目针对HSV-2抑制IFN-β产生的特性及IFN-β在抑制HIV-1黏膜感染中的重要性，拟在分子和黏膜细胞水平阐明ICP27抑制IFN-β产生的机制，并通过构建ICP27缺失病毒进行验证；利用极化的人黏膜组织块模型探究HSV-2极早期蛋白抑制IFN-β产生对HIV-1早期黏膜感染的影响。本项目有助于揭示HSV-2逃逸宿主黏膜免疫的机制及研发针对HSV-2/HIV-1黏膜共感染的阻断策略。

HSV-2 is the major cause of genital herpes, increases the risk of HIV-1 sexual transmission, and can establish latency by evading the host immune system. We previously found that productive HSV-2 infection in mucosal tissues inhibited the expression of IFN-β, and that HSV-2 immediate-early protein ICP22 impaired the production of IFN-β by impeding the IRF3-mediated signaling pathway. However, ICP22-null HSV-2 did not completely loss the capability in suppressing IFN-β production. Our pilot study has identified the immediate-early protein ICP27 as a potent antagonist of IFN-β production, but the mechanism remains to be defined. Given the characteristics of HSV-2 in antagonizing IFN-β production and the significance of IFN-β in inhibiting HIV-1 mucosal infection, in this proposed project, we intend to elucidate how ICP27 impairs IFN-β production at molecular and mucosal levels and confirm the findings by constructing and testing ICP27-null HSV-2. Using a polarized human cervical explant model, we will further address the impact of HSV-2 infection on the production of IFN-β mediated by immediate-early proteins and consequently on HIV-1 early mucosal infection. The research outcomes would be important for not only understanding the mechanism of HSV-2 mucosal immune evasion but also the development of novel strategies to block HSV-2/HIV-1 mucosal co-infection.