Effect of HIV and IL28B on NK control of HCV

HIV和IL28B对HCV NK控制的影响

• 批准号: 8438728
• 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/8438728
• 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; 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; Outcome; 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; cytokine; improved; in vitro Assay; in vivo; innovation; insight; interferon alpha receptor; killer immunoglobulin-like receptor; novel; peripheral blood; receptor; 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的最常见原因。 HIV 合并感染和非洲血统与当前标准护理聚乙二醇化 IFN-α/利巴韦林 (PegIFN/RBV) 和 PegIFN/RBV/蛋白酶抑制剂 (PI) 疗法的反应受损有关。这些关联的潜在机制尚不清楚，但 IL28B (IFN-gamma3) 基因区域 SNP 基因型可能占种族关联的一半，而 HIV 相关的免疫损伤可能占 HIV 关联的一半。 IL28B 基因型被认为影响 IL28B 表达水平，但对其作用机制知之甚少。较新的含 PI 的疗法已将 HCV 基因型 1 持续病毒学应答 (SVR) 率提高至 70% 左右。然而，将 PI 与 PegIFN/RBV 结合的需要意味着对含有 PI 的治疗的反应仍然依赖于 IFN-α 和 IL28B。此外，难以治疗的人群（包括艾滋病毒和非洲裔）PegIFN/RBV/PI SVR 率可能<60%，需要创新策略。因此，研究 HIV、种族和 IL28B 基因型对 PegIFN/RBV/PI 治疗反应影响的机制是更好地预测治疗结果和确定改进疗法的关键。 IFN-α 对细胞功能有多种影响，包括直接激活自然杀伤 (NK) 细胞。 NK 细胞抑制性受体 KIR2DL3 与其较弱的结合配体 (HLA-C1) 结合与急性 HCV 感染的更大清除率相关，并且特定 NK 细胞杀伤性免疫球蛋白样受体 (KIR) 的表达也与对 IFN-α 治疗的反应相关。因此，NK 细胞可能在控制 HCV 中发挥作用。我们的新数据表明，较高的 CD16+56-NK 子集 IFN-α R 表达与较高的 IFN-α 诱导的 IFN-α 信号传导相关，可预测对基于 IFN-α 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）在病毒感染期间产生IFN-α，并直接激活NK细胞。 HIV 感染期间存在较低的 pDC 和 NK 子集频率以及对 IFN 的反应性。我们之前的数据表明 NK 和 pDC 的损伤导致 HIV 感染中 pDC-NK 相互作用受损。 HCV 感染期间 pDC 数量和功能也较低。每种感染中存在的缺陷是否会共同损害 HCV-HIV 共感染宿主控制 HCV 的能力尚不清楚。此外，IL28B 基因型是否是种族差异的 NK IFN-αR 表达水平和随后的信号传导的基础尚不清楚。 我们提出了一种新模型，可以从机制上深入了解 IL-28B、种族和 HIV 对基于 IFN-α 的 HCV 治疗反应的影响。阐明该模型的目的是确定更好的结果预测因子，改进难以治疗人群的治疗方案，更好地了解宿主与病毒的相互作用。在此应用中，我们将 1) 确定 IL28B、种族和 HIV 感染对 NK 和 pDC-NK 介导的体外 HCV 复制控制的影响； 2) 确定 HIV 和 HCV 相关的 IFN 依赖性 NK 功能损伤的机制； 3)确定IL28B相关的IFN-αR表达和HCV的IFN-α依赖性NK体外控制是否可以预测在HCV和HCV-HIV感染的情况下在PegIFN/RBV/PI治疗HCV期间HCV的体内控制。