Antiviral Role of APOBEC3 in HIV/HCV Coinfected Patients

描述（由申请人提供）：我申请指导研究科学家发展奖（K01）的目标是在转化艾滋病毒研究方面发展事业，将艾滋病毒/艾滋病领域的基础科学进展与治疗病毒感染的新策略的发展结合起来。根据我的研究计划，我将重点研究APOBEC3宿主因子的抗病毒活性和治疗潜力，重点研究apobecs介导的胞苷脱氨酶活性对HIV-1和丙型肝炎病毒（HCV）体内复制的抑制作用。我的最终目标是通过培养和应用我在进化生物学、群体遗传学和台式分子病毒学方面的专业知识，促进我们对病毒发病机制的理解，并概念化传染病管理的新方法。我将在一个杰出和特殊的研究环境中培训和开展拟议的研究。该环境将包括加州大学旧金山分校（UCSF）医学系、J. David Gladstone病毒学和免疫学研究所、旧金山退伍军人事务医疗中心（SFVAMC）和斯坦福大学医学院基因组技术中心。本研究计划利用与HIV/HCV合并感染个体中HCV疾病治疗相关的偶然同步性。目前丙型肝炎病毒感染的标准治疗是利巴韦林和免疫调节细胞因子干扰素-a （IFN-a）联合治疗。临床研究表明，IFN-a治疗除了对HCV有预期的抗病毒作用外，还能显著降低HIV-1病毒载量。最近的一些体外研究表明，IFN-a治疗强烈诱导抗病毒宿主因子APOBEC3的表达。我们建议在UCSF医学中心或SFVAMC接受IFN-a治疗的HIV/HCV共感染个体中，对APOBEC3活性对观察到的HIV-1和HCV病毒血症抑制的贡献进行表征。本研究的目的是评估APOBEC3活性作为新型抗病毒治疗策略的基础，因此与公共卫生和HIV和HCV感染的临床管理直接相关。

DESCRIPTION (provided by applicant): My goal in seeking a Mentored Research Scientist Development Award (K01) is to develop a career in translational HIV research, integrating basic scientific advances in the field of HIV/AIDS with the development of novel strategies to treat viral infection. As outlined in my research plan, I will focus on the antiviral activity and therapeutic potential of the APOBEC3 host factors, concentrating on the suppressive effect of APOBECS-mediated cytidine deaminase activity on HIV-1 and Hepatitis C virus (HCV) replication in vivo. My ultimate goal is to contribute to our understanding of viral pathogenesis and conceptualize new approaches to infectious disease management, by cultivating and applying my expertise in evolutionary biology, population genetics, and benchtop molecular virology. I will be training and conducting the proposed research in a distinguished and exceptional research environment. This environment will include the University of California San Francisco (UCSF) Department of Medicine, The J. David Gladstone Institute of Virology and Immunology, the San Francisco Veterans Affairs Medical Center (SFVAMC), and the Stanford University School of Medicine Genome Technology Center. This research proposal makes use of a fortuitous synchronicity associated with the treatment of HCV disease in HIV/HCV coinfected individuals. The current standard of treatment for HCV infection is combination therapy with ribavirin and the immunomodulatory cytokine interferon-a (IFN-a). Clinical studies demonstrate that IFN-a treatment results in a pronounced reduction in HIV-1 viral load in addition to its intended antiviral effect against HCV. A number of recent in vitro studies demonstrate that IFN-a treatment strongly induces the expression of the antiviral host factor APOBEC3. We propose to characterize the contribution of APOBEC3 activity to the observed suppression of HIV-1 and HCV viremia in an existing, extensively characterized cohort of HIV/HCV coinfected individuals undergoing IFN-a treatment at the UCSF Medical Center or SFVAMC. The objective of this study is to evaluate APOBEC3 activity as a foundation for novel antiviral treatment strategies, and is therefore directly relevant to public health and the clinical management of HIV and HCV infection.