Antiviral Role of APOBEC3 in HIV/HCV Coinfected Patients

描述(由申请者提供)：我寻求导师研究科学家发展奖(K01)的目标是在翻译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开发相结合。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，重点是APOBECs介导的胞苷脱氨酶活性在体内对HIV-1和丙型肝炎病毒(HCV)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、种群遗传学和台式分子病毒学方面的专业知识，帮助我们理解病毒的发病机制，并概念化新的传染病管理方法。我将在一个杰出和杰出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。这项研究建议利用与治疗HIV/丙型肝炎病毒混合感染者的丙型肝炎病毒疾病相关的偶然性同步性。目前治疗丙型肝炎病毒感染的标准是利巴韦林和免疫调节细胞因子干扰素-a(干扰素-a)的联合治疗。临床研究表明，干扰素-a治疗除了对丙型肝炎病毒有预期的抗病毒作用外，还能显著降低艾滋病毒-1病毒载量。最近的一些体外研究表明，干扰素-a治疗强烈诱导抗病毒宿主因子APOBEC3的表达。我们建议在加州大学旧金山分校医学中心或SFVAMC接受干扰素-a治疗的现有的、被广泛描述的艾滋病毒/丙型肝炎共感染人群中，表征APOBEC3活性对观察到的抑制艾滋病毒-1和丙型肝炎病毒血症的贡献。这项研究的目的是评估APOBEC3活性作为新的抗病毒治疗策略的基础，因此与公共卫生和艾滋病毒和丙型肝炎病毒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.