HCV-Host Interaction during Acute Hepatitis C

下面描述的研究是HCV合作研究中心的一部分， 了解急性HCV感染期间发生的生物学事件。值得注意的是，只有11种HCV蛋白可以阻碍先天性和获得性细胞防御，以促进病毒复制和存活。在目前的提案中，我们将描述HCV-宿主相互作用，包括肝细胞，自然杀伤细胞（NK）和树突状细胞（DC），有助于解决急性HCV感染。这个建议是故意集中在病毒决定因素，调节先天免疫在急性感染。事实上，HCV蛋白已显示在多个水平上与各种信号转导途径相互作用，包括干扰素α（IFN）信号转导的抑制、IFN诱导的蛋白的直接抑制和IFN诱导的蛋白的阻断。 调节因子（IRF）。特别是，HCV核心蛋白在人类细胞中具有许多相互作用，因此与HCV的持久性和发病机制密切相关。我们最近发现HCV核心蛋白调节IRF和IFN途径。引人注目的是，不同的HCV核心临床分离株在与IFN途径的相互作用中表现出异质性。该建议将检验HCV核心对先天性信号转导通路的差异调节影响急性HCV感染结果的假设。我们还将通过向细胞中加入重组核心蛋白或在细胞内表达核心蛋白来研究细胞外与细胞内的核心-宿主相互作用。目标1将从50名急性感染患者中产生重组核心蛋白，其中25名患者已消退感染，25名患者进展为慢性感染。将对核心基因进行测序，由基因组遗传学分析，并分析与急性胰腺炎结局的相关性。 感染然后将测试HCV核心对人肝细胞固有抗病毒途径的影响。在目的2中，将评估核心蛋白对自然杀伤细胞（NK）和树突状细胞（DC）中IFN信号传导的影响。目的3将确定急性感染期间NK和DC的抗病毒、促炎和免疫调节反应以及HCV核心蛋白暴露是否与急性感染的结果相关。了解HCV核心蛋白如何在细胞外和细胞内与先天性细胞防御途径相互作用，对于控制急性丙型肝炎，定义急性感染和结果的病毒和宿主标志物非常重要，并可能为治疗开发提供新的机会。

The research described below forms part of an HCV Cooperative Research Center focused on understanding the biological events that occur during acute HCV infection. It is remarkable that as few as 11 HCV proteins can thwart innate and acquired cellular defenses to promote virus replication and survival. In the current proposal, we will characterize HCV-host interactions involving hepatocytes, natural killer (NK) and dendritic cells (DC) that contribute to the resolution of acute HCV infection. This proposal is intentionally focused on viral determinants that regulate innate immunity during acute infection. Indeed, HCV proteins have been shown to interact with various signal transduction pathways at multiple levels including inhibition of interferon alpha (IFN) signal transduction, direct inhibition of IFN-induced proteins, and blockade of IFN regulatory factors (IRF). In particular, the HCV core protein has many interactions in human cells, and hence is strongly implicated in HCV persistence and pathogenesis. We have recently found that the HCV core protein modulates IRF and IFN pathways. Strikingly, different clinical isolates of HCV core display heterogeneity in interaction with IFN pathways. This proposal will test the hypothesis that differential modulation of the innate signal transduction pathways by HCV core affects the outcome of acute HCV infection. We will also examine extracellular versus intracellular core-host interactions by adding recombinant core protein to cells or expressing core within cells. Aim 1 will generate recombinant core proteins from 50 acutely infected patients, 25 who resolve infection, and 25 who progress to chronicity. Core genes will be sequenced, analyzed by phylogenetics, and analyzed for correlations with outcome of acute infection. The effect of HCV core on human hepatocyte innate antiviral pathways will then be tested. In Aim 2, the effect of core protein on IFN signaling in natural killer (NK) and dendritic cells (DC) in will be evaluated. Aim 3 will determine whether NK and DC antiviral, pro-inflammatory and immunodulatory responses during acute infection and HCV core protein exposure correlate with outcome of acute infection. Understanding how the HCV core protein interacts extracellularly and intracellularly with innate cellular defense pathways is important for controlling acute hepatitis C, for defining viral and host markers of acute infection and outcome, and may afford new opportunities for therapeutic development.