Molecular Basis of Interferon Response in HCV

描述(由申请者提供)：这项以患者为导向的研究职业发展奖的总体目标是将候选人在以患者为导向的研究方面的背景与分子病毒学方面的新培训相结合，以了解干扰素反应在慢性丙型肝炎(丙型肝炎)治疗中的分子基础。丙型肝炎感染是美国临床肝病的主要原因。丙型肝炎病毒感染的干扰素治疗反应差异很大，在艾滋病毒感染患者和非裔美国人患者中尤其糟糕。在这项资助中，候选人将研究干扰素对代表一系列临床情景的患者在治疗期间丙型肝炎病毒动力学的影响。我们假设，NS5A区的序列变异和丙型肝炎病毒准种的多样性影响干扰素治疗引起的第一阶段斜率(下降)。为了验证这一假设，我们将在相同数量的非裔美国人和高加索人中，仔细检查感染了丙型肝炎病毒的患者和没有感染艾滋病毒的患者在早期时间点的病毒动力学，以确定那些初始干扰素反应快与慢的人。接下来，使用分子克隆和测序技术，我们将确定在干扰素治疗开始之前和在初始干扰素剂量后的相同早期时间点，丙型肝炎病毒基因组的复杂性和多样性。对每个克隆的整个NS5A区域进行测序将被用于利用生物信息学技术将特定突变与第一阶段斜率以及基因组复杂性和多样性相关联。在对干扰素治疗有不同反应率的人群中，对干扰素治疗过程中早期病毒动力学和NS5A分子变化的表征可能为以改善治疗反应为目标的干扰素作用机制提供新的见解。将分子病毒学方面的深入培训与候选人在以患者为中心的研究、艾滋病毒医学和肝病学方面的强大背景相结合，将使她为成为艾滋病毒/丙型肝炎病毒共同感染领域的独立研究员做好准备。

DESCRIPTION (provided by applicant): The overall objective of this Mentored Patient-Oriented Research Career Development Award is to integrate the candidate's background in patient-oriented research with new training in molecular virology to understand the molecular basis of interferon response in the treatment of chronic hepatitis C (HCV). Hepatitis C infection is the leading cause of clinical liver disease in the U.S. Interferon treatment responses vary greatly in HCV infection, and are particularly poor in HIV-infected and African-American patients. In this grant, the candidate will examine the effect of interferon on viral kinetics of HCV during therapy in patients representing a range of clinical scenarios. We hypothesize that sequence variation in the NS5A region and the diversity of HCV quasispecies influence the 1st phase slope (decline) induced by interferon therapy. To test this hypothesis, we will closely examine the viral kinetics at early time points in HCV-infected patients with and without HIV among an equal number of African Americans and Caucasians to identify those with rapid vs. slower initial interferon responses. Next, using molecular cloning and sequencing techniques, we will determine the complexity and diversity of the HCV genome prior to initiation of interferon therapy and at these same early time points after initial interferon dosing. Sequencing the entire NS5A region of each clone will be used to correlate specific mutations with 1st phase slope and with genomic complexity and diversity using bioinformatics techniques. Characterization of early viral kinetics and NS5A molecular changes during interferon therapy in populations that have different response rates to interferon therapy may provide novel insights into mechanisms of interferon action with the goal of improving treatment responses. Combining in-depth training in molecular virology with the candidate's strong background in patient-oriented research, HIV medicine, and hepatology will prepare her to become an independent investigator in the area of HIV/HCV co-infection.