VP22或其它病毒蛋白经TPPP1抑制HDAC6促进微管乙酰化利于HSV-1胞内运输的机理研究

Herpes simplex virus type 1 (HSV-1) is an important human pathogenic virus. It is urgent to develop novel antiviral targets because of the singleness of clinically used drugs and the emergence of drug resistant strains. Virus life cycle achievement depend on host factors, thus host factors virus required are promising therapeutic targets to develop novel, safety, and efficient anti-virus drugs. In our recent research(unpublished), we found that inhibiting HDAC6 by siRNA could induce microtubule acetylation and significantly promote the infection of HSV-1 in neuronal cells and over-expression of HDAC6 could inhibit the acetylation of tubulin and block the infection of HSV-1, while the detailed regulated mechanisms that HDAC6 participated in HSV-1 infection remains uncertain. We also found that TPPP1 upregulated significantly in the context of HSV-1 infection and VP22 overexpression, and HSV-1 infection enhanced the interaction between HDAC6 and TPPP1. Therefore, we hypothesize that HSV-1 may inhibit HDAC6 to facilitate microtubule acetylation through regulation of TPPP1 via viral factors or solely with its factors to enhance viral infection. In this project, we will explore the detailed regulation mechanisms that virus inhibited HDAC6 to enhance microtubule acetylation in HSV-1 infections through the viral factors (especially VP22) on TPPP1 molecular regulation pathways or directly on HDAC6 regulation by a series of experiments in vivo and in vitro, such as HDAC6 inhibition, gene silencing and over-expression, gene knockout, cutaneous mouse encephalitis and skin infection model, which will provide the theoretical foundation for the understanding and development of HDAC6 associated pathways as novel anti-HSV-1 targets.

单纯疱疹病毒1型（HSV-1）是重要的人类致病病毒，目前治疗药物单一且耐药愈发严重，急需探寻抗病毒新靶点。HSV-1感染依赖于宿主，深入研究宿主蛋白参与病毒感染的分子机制，有助于挖掘新的抗病毒靶点。申请人前期研究发现沉默HDAC6会显著上调乙酰化微管并促进HSV-1感染，且过表达HDAC6下调乙酰化微管并抑制其感染，但HDAC6参与HSV-1感染的分子机制尚不明确。HSV-1感染或病毒蛋白VP22可上调HDAC6调控蛋白TPPP1的表达，并增强HDAC6和TPPP1的结合。据此我们推测VP22或其它病毒蛋白可经TPPP1抑制HDAC6，进而促进微管乙酰化利于HSV-1感染。本研究拟利用HDAC6基因敲除小鼠疱疹病毒性脑炎模型结合基因沉默和过表达等技术从体内外深入探究HDAC6参与HSV-1感染的功能及分子机制，以期为HDAC6相关通路作为新型抗HSV-1药靶提供理论基础和实验依据。

单纯疱疹病毒1型（HSV-1）是重要的人类致病病毒，目前治疗药物单一且耐药愈发严重，.急需探寻抗病毒新靶点。HSV-1感染依赖于宿主，深入研究宿主蛋白参与病毒感染的分子机制，有助于挖掘新的抗病毒靶点。申请人前期研究发现沉默HDAC6会显著上调乙酰化微管并促进HSV-1感染，且过表达HDAC6下调乙酰化微管并抑制其感染，但HDAC6参与HSV-1感染的分子机制尚不明确。HSV-1感染或病毒蛋白VP22可上调HDAC6调控蛋白TPPP1的表达，并增强HDAC6和TPPP1的结合。据此我们推测VP22或其它病毒蛋白可经TPPP1抑制HDAC6，进而促进微管乙酰化利于HSV-1感染。本研究拟利用HDAC6基因敲除小鼠疱疹病毒性脑炎模型结合基因沉默和过表达等技术从体内外深入探究HDAC6参与HSV-1感染的功能及分子机制，以期为HDAC6相关通路作为新型抗HSV-1药靶提供理论基础和实验依据。

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