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）是美国慢性病毒肝炎的最常见原因。 HIV共感染和非洲血统与对当前护理标准的PEGYPEN-ALPHA/RIBAVIRIN（PEGIFN/RBV）和PEGIFN/RBV/RBV/蛋白酶抑制剂（PI）疗法的反应受损有关。尽管IL28B（IFN-GAMMA3）基因区域SNP基因型可能占种族关联的一半，而与HIV相关的免疫障碍可能占HIV协会，但这些关联的机制尚不清楚。 IL28B基因型被认为会影响IL28b表达水平，尽管对作用机理知之甚少。较新的含PI治疗的HCV基因型1持续病毒反应（SVR）率提高到70％左右。但是，将PI与PEGIFN/RBV结合的需求意味着对含PI含量治疗的反应仍然是IFN-Alpha，而IL28B依赖于IFN-Alpha。此外，很难治疗人口（包括艾滋病毒和非洲血统）PEGIFN/RBV/PI SVR率可能<60％，需要创新的策略。因此，研究HIV基础机制，种族和IL28B基因型对PEGIFN/RBV/PI治疗反应的影响是更好地预测治疗结果并确定改善疗法的关键。 IFN-α对细胞功能有许多影响，包括直接杀手（NK）细胞激活。 NK细胞抑制受体KIR2DL3与其较弱的结合配体（HLA-C1）结合使用，与急性HCV感染的清除率更大，并且特异性NK细胞杀伤剂类似于受体（KIR）的表达也与对IFN-Alpha疗法的反应有关。因此，NK细胞可能在控制HCV中起作用。我们的新数据表明，较大的CD16+56- NK子集IFN-Alpha R表达与较大的IFN-Alpha诱导的IFN-Alpha信号相关，可预测对基于IFN-Alpha的HCV疗法的反应，并且在种族上是种族和IL28B基因型。 浆细胞样树突状细胞（PDC）在病毒感染过程中产生IFN-α，并直接激活NK细胞。在HIV感染期间，PDC和NK子集的频率和对IFN的响应性存在。我们以前的数据表明，NK和PDC的损害都会导致HIV感染中PDC-NK相互作用受损。在HCV感染期间，PDC的数量和功能也较低。每个感染中存在的缺陷是否在损害HCV-HIV共感染的宿主控制HCV的能力中的缺陷尚不清楚。另外，IL28B基因型是否构成种族不同的NK IFN-Alphar表达水平以及随之而来的信号传导尚不清楚。 我们提出了一个新型模型，该模型可以对IL-28B，种族和HIV对基于IFN-Alpha的HCV治疗反应的影响有所了解。阐明该模型旨在确定更好的预测预测因素，改善难以治疗人群的治疗选择，更好地理解宿主病毒相互作用。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HCV复制控制的影响； 2）确定IFN依赖性NK功能中HIV和HCV相关损伤的基础机制； 3）确定IL28b在体外对HCV的IFN-Alphar表达和IFN-Alpha依赖性NK控制是否可以预测HCV和HCV-HIV感染的HCV期间HCV期间HCV的体内HCV的体内控制。