Modulation of HCV Gene Expression

描述（由申请人提供）：丙型肝炎病毒（HCV）构成公共卫生威胁。重要的是要确定病毒因素，阻碍自然防御和促进治疗失败。在一项横断面研究中，我们最近发现病毒复制与针对HCV新型替代阅读框蛋白（ARFPs）的抗体存在之间存在反比关系。arfp是我们小组之前发现的。抗arfp抗体的峰值表明，当HCV复制受到抑制时，arfp的产生增加。抗arfp抗体患者的HCV RNA在假定的顺式调控元件（CRE）中发生突变，称为末端茎环，我们之前也发现了这种RNA结构。我们最近的研究结果表明，arfp可能有助于HCV在不利条件下存活，并表明cre可能控制arfp的产生。提出的研究是基于我们最近的数据和其他数据，这些数据表明晚期肝硬化和肝癌患者的HCV rna在末端茎环中有突变。

DESCRIPTION (provided by applicant): The hepatitis C virus (HCV) poses a public health threat. It is important to identify viral factors that thwart natural defenses and contribute to treatment failure. In a cross sectional study, we recently found an inverse relationship between viral replication and the presence of antibodies directed against HCV's novel alternate reading frame proteins (ARFPs). ARFPs were discovered previously by our group. The spike of anti-ARFP antibodies suggests that production of ARFPs is increased when HCV replication is inhibited. HCV RNAs of patients with anti-ARFP antibodies have mutations in a putative cis regulatory element (CRE) called the Terminal Stem-loops, an RNA structure we also discovered previously. Our recent results suggest that ARFPs may help HCV survive adverse conditions, and indicate that CREs may control the production of ARFPs. The proposed studies are based on our recent data, and on data of others showing that HCV RNAs of patients with advanced cirrhosis and liver cancer have mutations in the Terminal Stem-loops. Experiments in Aim I test the hypothesis that effective anti-viral responses induced by IFN/ribavirin treatment are marked by a rise in immune responses to ARFPs. HCV RNA and anti-ARFP antibody levels, and the stimulation index (SI) and phenotype of peripheral blood mononuclear cells will be compared before, during, and after treatment. Experiments in Aim 2 test the hypothesis that mutations in the Terminal Stem-loops element accumulate during IFN/ribavirin treatment and during progression to advanced liver disease and liver cancer, modulating its function and increasing production of ARFPs. New software will be developed and applied to an expanded dataset of mutations, and the structure/function relationships of the Terminal Stem-loops will be defined. New information about HCV's adaptive mechanisms and pathways of gene expression will emerge from these studies and will advance the development of new drugs and vaccines for HCV.