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）是美国最常见的慢性病毒性肝炎病因。HIV合并感染和种族与基于IFN-a的HCV治疗（Peg-IFN-a/利巴韦林和Peg-IFN-a/利巴韦林/蛋白酶抑制剂）的反应受损相关。这些关联的机制尚不清楚，尽管IL28B基因型可能占种族关联的一部分。IFN-a对细胞功能有许多影响，包括直接自然杀伤（NK）细胞活化。NK细胞抑制受体KIR2DL3及其较弱的结合配体（HLA-C1）与急性HCV感染的清除相关，而激活受体KIR3DS1和适当的配体（HLA-Bw4-80ile）与HIV感染的缓慢进展相关。NK细胞KIRs也与对基于IFN-a的HCV治疗的反应相关。因此，NK细胞可能在控制HCV和HIV感染中发挥作用。我们的新数据表明，CD16+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治疗的反应，并且与种族和IL28B基因型相关。浆细胞样树突状细胞（pDC）在病毒感染过程中产生IFN-a，直接激活NK细胞。HIV感染期间存在较低的pDC和NK亚群频率和功能，包括NK对IFN-a的反应受损。我们的数据表明，NK和pDC功能的损伤导致HIV感染期间pDC-NK相互作用受损。丙型肝炎病毒感染期间也存在pDC数目和功能的改变。是否每一种感染都存在缺陷，从而削弱了HCV- hiv共感染宿主控制HCV感染的能力，目前尚不清楚。此外，IL28B基因型是否影响不同种族NK IFN-aR表达水平及其信号传导尚不清楚。我们提出了一种新的模型，可以从机制上理解IL-28B、种族和HIV介导的对基于IFN-a的HCV治疗反应的影响。该模型的研究旨在为改善难以治疗的HCV感染亚群（HIV合并感染和非洲人后裔）的治疗方案提供基础，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IL28B、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Aim 2中，我们将确定在HCV和HCV/HIV感染的情况下，在IFN-a/RBV/bocepravir治疗HCV期间，IL28B相关的IFN-aR表达和IFN-a依赖性NK体外控制HCV是否预测体内控制HCV。这些研究的总体目标是为难以治疗的HCV感染人群确定未来治疗设计的新靶点，并对宿主控制慢性病毒感染的机制有更广泛的了解。

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.