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　　南加州大學(xué)的研究人員已經(jīng)發(fā)現(xiàn)了丙型肝炎病毒進(jìn)入肝細(xì)胞的觸發(fā)機(jī)制——該機(jī)制揭示這種嚴(yán)重的和可能致命的病毒怎樣開始損害肝臟。該研究結(jié)果，發(fā)表在生物化學(xué)雜志，這項(xiàng)研究可以給科學(xué)家指明今后病毒治療的發(fā)展方向。

　　在丙型肝炎病毒（HCV）感染的早期階段，研究人員發(fā)現(xiàn)，該病毒結(jié)合到肝細(xì)胞表面的受體上，激活PI3K和AKT，這兩種蛋白質(zhì)控制細(xì)胞生長和代謝，使得HCV進(jìn)入肝細(xì)胞。

　　“當(dāng)這兩種蛋白因子被激活，他們引發(fā)一連串的反應(yīng)，改變感染細(xì)胞的生理，之后，通過繼續(xù)破壞這一途徑，病毒可使肝細(xì)胞易感，最終發(fā)展為癌變。”相關(guān)作者James Ou，美國凱克醫(yī)學(xué)院的分子微生物學(xué)和免疫學(xué)教授指出。

　　在美國HCV攜帶者有400萬，通常，人們并不知道他們攜帶病毒，直到他們已經(jīng)有一些肝臟損傷，這可能需要許多年的發(fā)展。同時(shí)，該病毒可以導(dǎo)致嚴(yán)重的和致命的肝臟疾?。焊斡不?，慢性、退行性疾??；癌癥以及器官衰竭。大約20%的丙型肝炎患者會出現(xiàn)嚴(yán)重的肝硬化，可能需要肝移植，約5%的患者20到30年后發(fā)展為肝癌。

　　Ou研究丙型肝炎病毒20年，乙型病毒性肝炎30年。最新的研究反映了他對于理解這些病毒和他們的宿主細(xì)胞之間的相互作用，以及它們?nèi)绾螌?dǎo)致肝癌的長期興趣。

　　“下一步，我們剛剛開始的，是了解PI3K-AKT途徑激活是如何使HCV進(jìn)入細(xì)胞的，”Ou說，“這項(xiàng)研究確定了一個(gè)發(fā)展新的抗-HCV藥物的新靶標(biāo)。打破PI3K-AKT途徑的化合物被期望能阻止病毒進(jìn)入肝細(xì)胞，使病毒消失。”

　　Transient Activation of the PI3K-AKT Pathway by Hepatitis C Virus to Enhance Viral Entry.

　　J Biol Chem 2012 Dec 7;287(50):41922-30 PMID:23095753

　　Liu Z,Tian Y,Machida K,Lai MM,Luo G,Foung SK,Ou JH

　　The PI3K-AKT signaling pathway plays an important role in cell growth and metabolism. Here we report that hepatitis C virus (HCV) transiently activates the PI3K-AKT pathway. This activation was observed as early as 15 min postinfection, peaked by 30 min, and became undetectable at 24 h postinfection. The activation of AKT could also be mediated by UV-inactivated HCV, HCV pseudoparticle, and the ectodomain of the HCV E2 envelope protein. Because antibodies directed against CD81 and claudin-1, but not antibodies directed against scavenger receptor class B type I or occludin, could also activate AKT, the interaction between HCV E2 and its two co-receptors CD81 and claudin-1 probably triggered the activation of AKT. This activation of AKT by HCV was important for HCV infectivity, because the silencing of AKT by siRNA or the treatment of cells with its inhibitors or with the inhibitor of its upstream regulator PI3K significantly inhibited HCV infection, whereas the expression of constitutively active AKT enhanced HCV infection. The PI3K-AKT pathway is probably involved in HCV entry, because the inhibition of this pathway could inhibit the entry of HCV pseudoparticle but not the VSV pseudoparticle into cells. Furthermore, the treatment of cells with the AKT inhibitor AKT-V prior to HCV infection inhibited HCV infection, whereas the treatment after HCV infection had no obvious effect. Taken together, our studies indicated that HCV transiently activates the PI3K-AKT pathway to facilitate its entry. These results provide important information for understanding HCV replication and pathogenesis and raised the possibility of targeting this cellular pathway to treat HCV patients.