The Host Response to Hepatitis C Virus

 描述(申请人提供)：控制从急性病毒感染到慢性病毒感染的病毒/宿主相互作用还不是很清楚。丙型肝炎病毒是一种慢性感染的模式RNA病毒，是当代的公共卫生问题。这项应用继续我们的重点是确定肝脏先天免疫的分子机制，它传递急性和慢性丙型肝炎病毒感染的结果。我们已经证明，视黄酸诱导基因-I(RIG-I)在识别和结合病原体相关分子模式(PAMP)后，启动了肝脏的先天性免疫反应。在急性感染期间，RIG-I对传播/方正(T/F)病毒基因组的这种识别导致其修饰和激活，将MAVS适配器蛋白结合到线粒体相关膜(MAM)上，并向限制感染的肝脏先天免疫防御发出信号。我们的初步研究显示，患者的T/F基因组在其PU/UC基序中显示出显著的变异，并且这种变异赋予RIG-I不同的识别和结合，从而允许逃避非自我识别。此外，我们还发现，RIG-I的信号转导依赖于RIG-I转位蛋白复合体的形成，该复合体促进RIG-I胞浆到膜的转位，从而促进MAV相互作用和MAM上的信号传递。我们的研究表明，这些活性是由rig-i的可逆酰化过程控制的，而且这个过程可能是通过 HDAC6蛋白作为天然免疫的RIG-I辅助因子。我们发现，丙型肝炎病毒通过以NS3/4A病毒蛋白酶为靶点的MAM来切割MAV并干扰RIG-I信号转导，从而逃避肝脏的天然免疫，从而促进慢性感染，这一作用依赖于MAM上稳定的NS3/4A-MAVS相互作用。这种相互作用的中断可以恢复先天免疫，以防止丙型肝炎病毒从急性向慢性转变。我们假设RIG-I途径的调节和肝脏的先天免疫是控制丙型肝炎病毒感染从急性向慢性转变的主要决定因素。因此，我们将进行以下研究：1)确定急性丙型肝炎病毒感染过程中病原体识别和T/F基因组固有免疫信号差异的RIG-I/PAMP相互作用；2)确定RIG-I乙酰化在转位蛋白组装和功能中的作用；3)确定介导相互作用的NS3/4A/MAVS界面，以控制RIG-I途径。

 DESCRIPTION (provided by applicant): The virus/host interactions that control the transition from acute to chronic virus infection are not well understood. Hepatitis C virus (HCV) is a model RNA virus of chronic infection and is a contemporary public health problem. This application continues our focus on defining the molecular mechanisms of hepatic innate immunity that impart acute to chronic HCV infection outcome. We have shown that retinoic acid inducible gene-I (RIG-I) initiates the hepatic innate immune response upon recognition and binding of the pathogen associated molecular pattern (PAMP) consisting of 5' triphosphate and the poly-uridine/cytosine (pU/UC) motif within the HCV RNA. During acute infection this recognition of the transmission/founder (T/F) viral genome by RIG-I results in its modification and activation to bind the MAVS adaptor protein on mitochondria-associated membranes (MAM) and signal hepatic innate immune defenses that restrict infection. Our preliminary studies now reveal that T/F genomes from patients exhibit remarkable variation within their pU/UC motif, and that this variation imparts differential recognition and binding by RIG-I that allows escape from non-self-recognition. Moreover, we have found that signaling by RIG-I is dependent on formation of a RIG-I translocon protein complex that facilitates RIG-I cytosol-to-membrane translocation for MAVS interaction and signaling on the MAM. Our studies now reveal that these activities are governed by the reversible acteylation of RIG-I, and that this process is likely controlled through the HDAC6 protein as a RIG-I cofactor of innate immunity. We show that HCV evades hepatic innate immunity via MAM targeting by the NS3/4A viral protease to cleave MAVS and disrupt RIG-I signaling, thereby facilitating chronic infection, and this action is dependent on stable NS3/4A- MAVS interaction on the MAM. Disruption of this interaction restores innate immunity to prevent acute to chronic HCV transition. We hypothesize that regulation of the RIG-I pathway and hepatic innate immunity are major determinants controlling the acute to chronic transition of HCV infection. We will therefore conduct studies to: 1) Define the RIG-I/PAMP interactions of pathogen recognition and differential innate immune signaling from T/F genomes during acute HCV infection; 2) Determine the role of RIG-I acetylation in translocon assembly and function; 3) Identify the NS3/4A/MAVS interface that mediates interaction to control the RIG-I pathway.