小分子化合物CD437增强体外HBV感染的分子机制研究及其应用

高效支持乙肝病毒(HBV)感染的细胞模型对乙肝新药发展与科学问题研究至关重要。外源表达人NTCP的HepG2细胞(HepG2-NTCP)是目前常用的HBV体外感染模型，其操作简便，稳定性好；但要求感染病毒滴度高，对病人血清来源HBV感染率低。我们发现化合物CD437能大幅增强人HepG2-NTCP和鼠Hepa1-6-NTCP的HBV易感性，并使HepG2-NTCP支持感染者带毒血清的直接感染，有助于研究血清HBV感染力的临床意义。我们已筛选到可能与CD437增强HBV感染相关的表达差异基因，拟在本课题中深入研究其作用和机制，以期发现新的影响乙肝感染宿主因子和潜在治疗靶标。此外，我们将对比乙肝感染者血清在CD437/HepG2-NTCP和其他体内外模型上的感染表征差异，以验证其用于临床样本感染力测试的可靠性。预期成果将为发展支持临床样本分析、药物筛选和乙肝基础研究的新型细胞模型提供科学依据。

Robust cell models supporting efficient HBV infection are essentially important for HBV drug developments and basic researches. Currently, human NTCP-reconstituted HepG2 cell (HepG2-NTCP) is commonly used for in vitro HBV infection system. Compared with other system, the NTCP-reconstituted in vitro HBV infection system is more convenient and reproducible, but requires a high-titer of virus incubation and only showed limited infectious efficiency to patient’s serum derived HBV. Our previous studies has revealed a small-molecular compound of CD437 could dramatically improve HBV infection performance on both human HepG2-NTCP and mouse Hepa1-6-NTCP cells. CD437-treatment enables HepG2-NTCP to support direct infection assay using HBV-contained serum specimens derived from HBV carriers, and therefore facilitates investigations on the clinical significance of HBV infectivity of patient’s serum. We have identified several differentially expressed gene candidates which possibly associated with CD437-mediated improvements on in vitro HBV infection. This proposal aimed to reveal new host factors and potential therapeutic targets via investigations on the roles and mechanisms of the host targets of CD437-enhanced in vitro HBV infection. The expected results of the proposal may provide scientific basis in developing novel HBV cell models supporting infectivity assay of clinical samples, drug screening and HBV-related fundamental researches.