PLoS Pathog：揭示乙肝病毒在人体长存的分子机制

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原帖由ipsvirus 2012-3-30 14:00 发表于老论坛




3月15日，国际病毒学顶级学术期刊PloS Pathogens 在线发表了中国科学技术大学生命科学学院魏海明和田志刚教授研究组的科研成果----TGF-b1 Down-Regulation of NKG2D/DAP10 and 2B4/SAP Expression on Human NK Cells Contributes to HBV Persistence。揭示了乙型肝炎病毒逃避自然杀伤细胞的攻击,进而在人体长期存在的分子机制。文章第一作者是中国科学技术大学生命科学学院博士生孙成，通讯作者是魏海明和田志刚教授。

我国是乙型肝炎病毒感染大国, 约有1.2亿人被乙肝病毒感染, 母婴传播是乙肝病毒感染的主要途径, 新生儿被感染后可在体内持续存在数年, 在青春期后可陆续发病。迄今为止，尚不清楚乙肝病毒逃避机体免疫系统的攻击，并在体内长期生存的原因。

本研究对154例乙肝病毒携带者和乙肝病人进行系统免疫学研究，发现乙肝病毒持续感染者体内主要抗病毒免疫细胞—--自然杀伤细胞数量明显减少，残存的自然杀伤细胞也难以被激活，激发该细胞发挥杀伤病毒作用的双信号分子NKG2D/DAP10和2B4/SAP明显减弱，进一步分析原因发现，乙肝病毒携带者体内大量存在一种免疫抑制因子----转化生长因子β1（TGF-β1），该因子可导致自然杀伤细胞发生细胞周期阻滞，从而失去抗病毒作用，用抗转化生长因子β1抗体进行处理，可较大程度恢复自然杀伤细胞的功能。

该研究对理解乙型肝炎病毒在人体内长期持续感染的机制有较大帮助。

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TGF-β1 Down-Regulation of NKG2D/DAP10 and 2B4/SAP Expression on Human NK Cells Contributes to HBV Persistence

Cheng Sun, Binqing Fu,Yufeng Gao, Xiaofeng Liao, Rui Sun,Zhigang Tian, Haiming Wei

The mechanism underlying persistent hepatitis B virus (HBV) infection remains unclear. We investigated the role of innate immune responses to persistent HBV infection in 154 HBV-infected patients and 95 healthy controls. The expression of NKG2D- and 2B4-activating receptors on NK cells was significantly decreased, and moreover, the expression of DAP10 and SAP, the intracellular adaptor proteins of NKG2D and 2B4 (respectively), were lower, which then impaired NK cell-mediated cytotoxic capacity and interferon-γ production. Higher concentrations of transforming growth factor-beta 1 (TGF-β1) were found in sera from persistently infected HBV patients. TGF-β1 down-regulated the expression of NKG2D and 2B4 on NK cells in our in vitro study, leading to an impairment of their effector functions. Anti-TGF-β1 antibodies could restore the expression of NKG2D and 2B4 on NK cells in vitro. Furthermore, TGF-β1 induced cell-cycle arrest in NK cells by up-regulating the expression of p15 and p21 in NK cells from immunotolerant (IT) patients. We conclude that TGF-β1 may reduce the expression of NKG2D/DAP10 and 2B4/SAP, and those IT patients who are deficient in these double-activating signals have impaired NK cell function, which is correlated with persistent HBV infection.