HAART过程中HCV复制增强与肝细胞MAVS抗病毒通路的关系研究

Several investigations and our previous work also indicated that, during HAART (highly active anti-retroviral therapy) without anti-HCV treatment, HCV viral load increased in HIV/HCV co-infected patients, although the anti HIV effect is obvious. The details of mechanisms are still unknown. In 2005, mitochondrial antiviral signaling protein ( MAVS ) had been found, and recent studies confirmed that MAVS plays an important role in virus-host relationship during HCV infection. MAVS inhibits the replication of HCV through promoting the expression of interferon and ISG, and HCV enhances own replication by it's cleavage of MAVS. In recent years, researchers had confirmed that HAART has mitochondrial toxicity, and reduced cellular mitochondrial DNA copy number and damaged the expression of functional genes of mitochondria, then led to increased blood lactic acid and fatty degeneration of liver damage. Our hypothesis of this researching is: HAART induced mitochondrial damage will weaken liver cell's MAVS antiviral signaling pathway activity, so that HCV replication will increases. This study is intended to HIV / HCV co-infected patients and HCV infection cell model for object, the aim is to clear the relationship of HAART's mitochondrial damage and HCV replication and MAVS signaling pathways in hepatic cells, to clarify the mechanism of increased HCV replication in HIV / HCV co-infected patients during HAART, in order to explore the best antiviral treatment of HIV/HCV co-infection.

研究证实，HIV/HCV合并感染者在HAART开始后，虽抗HIV效果明显，但较HIV单一感染者肝损伤严重，且血中HCV载量增加，具体机制尚不清楚。2005年发现的线粒体抗病毒蛋白（MAVS）被新研究证实在HCV感染与宿主防御的相互关系中起重要作用：HCV感染时MAVS通过促进干扰素和ISG的表达抑制HCV复制，而HCV又通过裂解MAVS导致自身复制增强。近年来发现，HAART具有线粒体毒性，可导致细胞线粒体DNA拷贝数降低和功能基因表达受损等，引起血乳酸增高和肝脂肪变性等损害。我们推论：HAART引起的线粒体损伤会导致MAVS肝细胞抗病毒信号通路活性减弱，从而使HCV复制增加。本研究拟以HIV/HCV共感染患者和HCV感染细胞模型为对象，明确HAART中线粒体损伤与HCV复制的关系以及其中MAVS信号通路所起的作用，阐明HAART中HCV复制增加的机制，为探索最佳抗病毒治疗方案提供依据。

HIV/HCV合并感染者虽然抗HIV疗效明显但抗HCV疗效不佳。近年的研究证实：长期HAART会导致线粒体功能受损，而线粒体是介导宿主抗病毒天然免疫中的关键环节之一。在本课题研究中，我们以HIV、HCV单一及合并感染的临床患者为对象，首先研究了HAART前及过程中线粒体损伤的动态变化及在此过程中MAVS的表达水平，然后以内源性干扰素应答水平（本研究中以干扰素刺激基因APOBEC3G、ISG-15、MxA的表达水平为标志）和炎性反应水平（本研究中以IFN-r和IP-10的表达水平为标志）为指标，比较了HIV和HCV两种病毒合并感染及HAART对线粒体介导的内源性抗病毒信号通路的影响。本研究揭示了HAAR对合并感染者的线粒体损伤特征及对线粒体途径介导的天然抗病毒免疫水平的影响，及后继抗HCV治疗效果与线粒体损伤和天然抗病毒免疫的关系，为优化HIV/HCV合并感染的临床治疗策略提供了理论依据。