单纯疱疹病毒（HSV）I和II型可潜伏于感觉神经元并从中激活引发疾病。潜伏是HSV无法治愈的关键。近年报道显示宿主miRNA可促使一些病毒潜伏，但人们对其如何影响HSV潜伏所知甚少。我们前期研究提示神经特异性宿主miR-138通过靶向病毒ICP0基因和未知宿主基因两种方式下调HSV复制或基因表达，故推测与其潜伏机制有关。本项目首先用培养细胞确定神经元中miR-138对病毒复制和基因表达的影响。然后构建miR-138敲除小鼠和表达及抑制miR-138的重组病毒，创建敲除、过表达和抑制miR-138三种情况下的小鼠潜伏感染模型，检测病毒复制和基因表达水平，观测小鼠免疫指标和症状，并与对照组比较。最后用PAR-CLIP和RNAseq技术识别miR-138的未知宿主靶基因，进而揭示其独立于ICP0促进潜伏的分子机制。结果将明确miR-138促进HSV潜伏的作用及机制，为治疗HSV潜伏感染提供思路。

Herpes simplex virus-1 and -2 (HSV-1 and HSV-2) can undergo latent infection in sensory neurons, from which the viruses can reactivate and cause disease. Latency is the key reason why HSV infections have yet to be cured. Recent studies have suggested that some host miRNAs can promote latency for some viruses, yet little is known about how host miRNAs affect HSV latency. Our previous research suggests that the neuron-specific host miRNA, miR-138, suppresses HSV-1 replication and gene expression, both by directly targeting the mRNA for the viral protein ICP0, and most likely by also targeting host mRNAs, leading to our hypothesis that these are mechanisms conserved between HSV-1 and HSV-2 that promote viral latency. The first aim of this project is to investigate the effects of miR-138 on HSV-1 and HSV-2 replication and gene expression in neuronal cultures. In the second aim, we plan to construct sensory neuron specific miR-138 knock-out mice as well as a recombinant HSV-1 that expresses either miR-138 or its antisense sequences. By comparing these mice and viruses with the corresponding control groups in a mouse model of latent infection, we will investigate the effects of miR-138 on levels of HSV-1 or HSV-2 replication and gene expression in mouse trigeminal ganglia, as well as on mouse immune responses and symptoms. In the third aim, we plan to identify the unknown host targets of miR-138 using PAR-CLIP and RNAseq techniques, followed by investigation of the molecular mechanisms by which miR-138 promotes HSV-1 and HSV-2 latency independently of ICP0. The results of this project should elucidate the role miR-138 plays in HSV latency, and might provide ideas on how to treat or even cure HSV latent infections.