Role of IL28B and HIV in NK Control of HCV

描述（由申请人提供）：丙型肝炎病毒（HCV）是美国慢性病毒性肝炎最常见的病因。HIV合并感染和种族与对基于IFN-α的HCV治疗（Peg-IFN-α/利巴韦林和Peg-IFN-α/利巴韦林/蛋白酶抑制剂）的应答受损相关。这些关联的机制尚不清楚，尽管IL 28 B基因型可能占种族关联的一部分。IFN-α对细胞功能有许多影响，包括直接的自然杀伤（NK）细胞活化。NK细胞抑制性受体KIR 2DL 3与其较弱的结合配体（HLA-C1）组合与急性HCV感染的清除相关，而活化性受体KIR 3DS 1和适当的配体（HLA-Bw 4 - 80 ile）与HIV感染的缓慢进展相关。NK细胞KIR也与对基于IFN-α的HCV疗法的应答相关。因此，NK细胞可能在控制HCV和HIV感染方面发挥作用。我们的新数据表明，CD 16 +56- NK亚群IFN-aR表达水平调节IFN-a信号传导，预测对基于IFN-a的HCV治疗的应答，并且与种族和IL 28 B基因型相关。浆细胞样树突状细胞（pDC）在病毒感染期间产生IFN-α，并直接激活NK细胞。在HIV感染期间存在较低的pDC和NK亚群频率和功能，包括受损的NK对IFN-α的应答。我们的数据表明NK和pDC功能的受损有助于HIV感染期间pDC-NK相互作用的受损。在HCV感染期间也存在改变的pDC数量和功能。目前尚不清楚每种感染中存在的缺陷是否会协同损害HCV-HIV共感染宿主控制HCV感染的能力。此外，IL 28 B基因型是否是种族不同的NK IFN-aR表达水平和随后的信号传导的基础尚不清楚。我们提出了一种新的模型，该模型有助于对IL-28 B、种族和HIV介导的对基于IFN-α的HCV治疗应答的影响的机制理解。对该模型的研究旨在为难以治疗的HCV感染亚组（HIV合并感染和非洲裔）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。我们将在目的1中确定IL 28 B、种族和HIV感染对NK和pDC-NK介导的HCV体外复制控制的影响。在目的2中，我们将确定在HCV和HCV/HIV感染的情况下，在IFN-α/RBV/bocepravir治疗HCV期间，体外HCV的IL 28 B相关的IFN-α R表达和IFN-α依赖性NK控制是否预测体内HCV控制。这些研究的总体目标是确定新的重点目标，为未来的治疗设计，在难以治疗的人群中的HCV感染的个人，并实现更广泛的了解机制的主机控制慢性病毒感染。 公共卫生相关性：治疗慢性HCV感染需要改进的疗法，更清楚地了解HCV治疗中IL 28 B基因型、HIV感染和遗传祖先的作用机制，可能有助于指导未来改进疗法的开发，特别是在难以治疗的人群中，如HI合并感染和非洲裔人群。目前的建议将调查IL 28 B基因型，HIV感染和遗传祖先在NK细胞和树突状细胞（浆细胞样亚群）-NK细胞介导的HCV控制的作用，总体目标是推进我们对IFN-γ期间宿主控制HCV的机制的理解，以及在其他慢性病毒感染期间宿主-病毒相互作用的机制。

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. PUBLIC HEALTH RELEVANCE: Improved therapies are needed for the treatment of chronic HCV infection, and a clearer understanding of the mechanism of action IL28B genotype, HIV infection and genetic ancestry in HCV therapy, is likely to help guide development of improved future therapies, especially in the setting of difficult to treat populations such as those with HI coinfection and African decent. The current proposal will investigate the role of IL28B genotype, HIV infection and genetic ancestry in NK cell and dendritic cell (plasmacytoid subset)-NK cell mediated control of HCV, with the overall goal of advancing our understanding of mechanisms involved in host control of HCV during IFN- , and in host-virus interactions during other chronic viral infections.