Role of IL28B and HIV in NK Control of HCV

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)是美国慢性病毒性肝炎最常见的原因。HIV混合感染和种族与基于干扰素-a的丙型肝炎病毒治疗(聚乙二醇化干扰素/利巴韦林和聚乙二醇化干扰素/利巴韦林/蛋白酶抑制剂)的反应受损有关。这些关联背后的机制尚不清楚，尽管IL28B基因可能是种族关联的一部分。干扰素-α对细胞功能有多种影响，包括直接自然杀伤(NK)细胞的激活。NK细胞抑制受体KIR2DL3及其较弱的结合配体(HLA-C1)与急性丙型肝炎病毒感染的清除有关，而激活受体KIR3DS1和适当的配体(HLA-Bw4-80ile)与HIV感染的缓慢进展有关。NK细胞KIR也与以干扰素-a为基础的丙型肝炎病毒治疗的应答有关。因此，NK细胞可能在控制丙型肝炎病毒和艾滋病病毒感染方面发挥作用。我们的新数据表明，CD16+56-NK亚群干扰素-AR的表达水平调节干扰素-α信号，预测对基于干扰素-α的丙型肝炎治疗的应答，并与种族和IL28B基因相关。浆细胞样树突状细胞(PDC)在病毒感染过程中产生干扰素-α，并直接激活NK细胞。在HIV感染过程中，PDC和NK亚群的频率和功能降低，包括NK细胞对干扰素-a的反应受损。我们的数据表明，在HIV感染过程中，NK和PDC功能的受损是PDC-NK相互作用受损的原因之一。在丙型肝炎病毒感染过程中，PDC的数量和功能也会发生改变。目前尚不清楚每种感染中存在的缺陷是否共同损害了合并感染丙型肝炎病毒的宿主控制丙型肝炎病毒感染的能力。此外，IL28B基因是否存在种族差异的NK干扰素-AR表达水平以及由此产生的信号转导尚不清楚。我们提出了一个新的模型，提供了对IL-28B、RACE和HIV介导的基于干扰素-a的丙型肝炎病毒治疗应答的机制理解。对这一模型的研究旨在为改进难以治疗的丙型肝炎病毒感染亚群(艾滋病毒合并感染和非洲血统)的治疗选择提供基础，并更广泛地了解NK介导的慢性病毒感染控制。在目标1中，我们将在体外确定IL28B、RACE和HIV感染对NK和PDC-NK介导的丙型肝炎病毒复制控制的影响。在目的2中，我们将确定在丙型肝炎病毒感染和丙型肝炎病毒感染的情况下，在干扰素-a/RBV/博卡拉韦治疗丙型肝炎病毒的过程中，IL-28B相关的干扰素-α的表达和体外对丙型肝炎病毒的依赖的NK控制是否可以预测体内丙型肝炎病毒的控制。这些研究的总体目标是为未来难以治疗的丙型肝炎病毒感染者群体的治疗设计确定新的焦点，并实现对宿主控制慢性病毒感染的基础机制的更广泛的理解。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States. HIV coinfection and race are associated with impaired response to IFN-a based HCV therapy (Peg-IFN-a/ribavirin and Peg-IFN-a/ribavirin/protease inhibitor). Mechanisms underlying these associations are not clear, though IL28B genotype likely accounts for a portion of the racial association. IFN-a has many effects on cell function, including direct natural killer (NK) cell activation. NK cell inhibitory receptor KIR2DL3 in combination with its weaker binding ligand (HLA-C1) are associated with clearance of acute HCV infection, while the activating receptor KIR3DS1 and the appropriate ligand (HLA-Bw4-80ile) are associated with slower progression of HIV infection. NK cell KIRs are also associated with response to IFN-a based HCV therapy. NK cells therefore likely play a role in control of both HCV and HIV infection. Our new data indicate CD16+56- NK subset IFN-aR expression level regulates IFN-a signaling, predicts response to IFN-a based HCV therapy, and is racially and IL28B genotype associated. Plasmacytoid dendritic cells (pDC) produce IFN-a during viral infection, and directly activate NK cells. Lower pDC and NK subset frequency and function are present during HIV infection, including impaired NK response to IFN-a. Our data indicate impairment in both NK and pDC function contributes to impaired pDC-NK interactions during HIV infection. Altered pDC numbers and function are also present during HCV infection. Whether defects present in each infection collaborate in impairing HCV-HIV co- infected host ability to control of HCV infection is not known. Additionally, whether IL28B genotype underlies racially disparate NK IFN-aR expression level and consequent signaling is unclear. We propose a novel model that lends mechanistic understanding of IL-28B, race and HIV mediated effects on IFN-a based HCV therapy response. Investigation of this model is intended to provide a foundation for improved therapy options in difficult to treat HCV infected subgroups (HIV co-infection and African descent), and a broader understanding of NK mediated control of chronic viral infection. We will in Aim 1 Determine the effect of IL28B, race, and HIV infection on NK and pDC-NK mediated control of HCV replication in vitro. In Aim 2 we will determine whether IL28B associated IFN-aR expression and IFN-a dependent NK control of HCV in vitro is predictive of in vivo control of HCV during IFN-a/RBV/bocepravir therapy for HCV in the setting of HCV and HCV/HIV infection. The overall goal of these studies is to identify novel targets of focus for future therapeutic design in difficult to treat populations of HCV infected individuals, and to achieve a broader understanding of mechanisms underlying host control of chronic viral infection.