Effect of HIV and IL28B on NK control of HCV

HIV和IL28B对HCV NK控制的影响

• 批准号: 8974298
• 负责人: Donald D Anthony
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974298
• 关键词: AIDS clinical trial group; Accounting; Activated Natural Killer Cell; Acute Hepatitis C; Affect; African; Antiviral Therapy; Antiviral resistance; Cell Count; Cell physiology; Cells; Chronic Hepatitis; Chronic viral hepatitis; Cirrhosis; Cytolysis; Data; Defect; Dendritic Cells; Elements; FCGR3B gene; Freezing; Frequencies; Gene Expression; Genes; Genetic Transcription; Genotype; Goals; HIV; HIV Infections; HIV/HCV; Health; Hepatitis C; Hepatitis C virus; Immune; Impairment; In Vitro; Infection; Interferon-alpha; Interferons; Investigation; Ligand Binding; Liver diseases; Measures; Mediating; Mediator of activation protein; Modeling; Mono-S; NK Cell Activation; Natural Killer Cells; Pathway interactions; Patients; Phenotype; Play; Population; Protease Inhibitor; Qualifying; Race; Resistance; Ribavirin; Risk; Role; SNP genotyping; Sampling; Signal Transduction; Staging; Testing; United States; Veterans; Viral; Virus Diseases; Virus Replication; base; chemokine; co-infection; cytokine; improved; in vitro Assay; in vivo; innovation; insight; interferon alpha receptor; killer immunoglobulin-like receptor; novel; outcome prediction; peripheral blood; predicting response; receptor; resistance gene; response; screening; standard of care; therapy outcome; virus host interaction

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States. HIV coinfection and African ancestry are associated with impaired response to current standard of care pegylated IFN-alpha/ribavirin (PegIFN/RBV) and PegIFN/RBV/protease inhibitor (PI) therapy. Mechanisms underlying these associations are not clear, though IL28B (IFN-gamma3) gene region SNP genotype likely accounts for half of the racial association and HIV-associated immune impairment likely accounts for the HIV association. IL28B genotype is thought to affect level of IL28B expression, though little else is known about the mechanism of action. Newer PI containing therapy has increased HCV genotype 1 sustained virologic response (SVR) rates to around 70%. However, the need to combine PIs with PegIFN/RBV means that response to PI containing therapy remains IFN-alpha and IL28B dependent. Moreover, difficult to treat population (including HIV and African descent) PegIFN/RBV/PI SVR rates are likely <60%, requiring innovative strategies. Therefore, investigation of the mechanism underlying HIV, race and IL28B genotype effect on PegIFN/RBV/PI therapy response is key to better predict therapy outcome, and identify improved therapies. IFN-alpha 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 greater clearance of acute HCV infection, and expression of specific NK cell killer immunoglobulin like receptors (KIRs) are also associated with response to IFN-alpha therapy. NK cells therefore likely play a role in control of HCV. Our new data indicate greater CD16+56- NK subset IFN-alpha R expression correlates with greater IFN-alpha induced IFN- alpha signaling, predicts response to IFN-alpha based HCV therapy, and is racially and IL28B genotype associated. Plasmacytoid dendritic cells (pDC) produce IFN-alpha during viral infection, and directly activate NK cells. Lower pDC and NK subset frequency and responsiveness to IFN are present during HIV infection. Our previous data indicate impairment in both NK and pDC contribute to impaired pDC-NK interactions in HIV infection. Lower pDC numbers and function are also present during HCV infection. Whether defects present in each infection combine in impairing HCV-HIV co-infected host ability to control of HCV is not known. Additionally, whether IL28B genotype underlies racially disparate NK IFN-alphaR expression level and consequent signaling is unclear. We propose a novel model that lends mechanistic insight into IL-28B, race and HIV effects on IFN-alpha based HCV therapy response. Elucidation of this model is intended to identify better outcome predictors, improved therapy options for difficult to treat populations, an better understand host-virus interactions. In this application we will 1) Determine the effect of IL28B, race, and HIV infection on NK and pDC-NK mediated control of HCV replication in vitro; 2) To identify the mechanism underlying HIV and HCV associated impairment in IFN dependent NK function; and 3) Determine whether IL28B associated IFN-alphaR expression and IFN-alpha dependent NK control of HCV in vitro is predictive of in vivo control of HCV during PegIFN/RBV/PI therapy for HCV in the setting of HCV and HCV-HIV infection.

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原因。HIV合并感染和非洲血统与对当前标准治疗聚乙二醇化IFN-α/利巴韦林（PegIFN/RBV）和PegIFN/RBV/蛋白酶抑制剂（PI）治疗的应答受损相关。这些关联的机制尚不清楚，尽管IL 28 B（IFN-γ 3）基因区域SNP基因型可能占种族关联的一半，HIV相关的免疫损伤可能占HIV关联的一半。IL 28 B基因型被认为影响IL 28 B表达水平，尽管对作用机制知之甚少。较新的含PI的治疗使HCV基因型1的持续病毒学应答（SVR）率增加到约70%。然而，需要将联合收割机PI与PegIFN/RBV组合意味着对含有PI的治疗的应答仍然依赖于IFN-α和IL 28 B。此外，难以治疗的人群（包括HIV和非洲裔）PegIFN/RBV/PI SVR率可能<60%，需要创新策略。因此，研究HIV、种族和IL 28 B基因型对PegIFN/RBV/PI治疗反应的潜在机制是更好地预测治疗结果和确定改进的治疗的关键。 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与其较弱结合配体（HLA-C1）的组合与急性HCV感染的更大清除相关，并且特异性NK细胞杀伤免疫球蛋白样受体（KIR）的表达也与对IFN-α治疗的应答相关。因此，NK细胞可能在控制HCV中发挥作用。我们的新数据表明更高的CD 16 +56- NK亚群IFN-α R表达与更高的IFN-α诱导的IFN-α信号传导相关，预测对基于IFN-α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亚群频率以及对IFN的反应性。我们以前的数据表明NK和pDC两者的损伤有助于HIV感染中pDC-NK相互作用的受损。在HCV感染期间也存在较低的pDC数量和功能。目前尚不清楚是否存在于每种感染联合收割机中的缺陷会损害HCV-HIV共感染宿主控制HCV的能力。此外，IL 28 B基因型是否是种族差异NK IFN-alphaR表达水平和随后信号传导的基础尚不清楚。 我们提出了一种新的模型，该模型有助于深入了解IL-28 B，种族和HIV对基于IFN-α的HCV治疗反应的影响。该模型的阐明旨在确定更好的结局预测因子，改善难以治疗人群的治疗选择，更好地了解宿主-病毒相互作用。在本申请中，我们将1）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; 2）鉴定HIV和HCV相关的IFN依赖性NK功能损伤的潜在机制;和3）确定是否IL 28 B相关的IFN-α R表达和IFN-γ表达。在HCV和HCV-HIV感染的情况下，HCV的体外α依赖性NK控制可预测HCV的PegIFN/RBV/PI治疗期间HCV的体内控制。