Antiviral Role of APOBEC3 in HIV/HCV Coinfected Patients

描述（由申请人提供）：我在寻求一个指导研究科学家发展奖（K 01）的目标是发展在转化艾滋病毒研究的职业生涯，整合在艾滋病毒/艾滋病领域的基础科学进步与新的战略发展，以治疗病毒感染。正如我的研究计划中所概述的，我将专注于APOBEC 3宿主因子的抗病毒活性和治疗潜力，专注于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，为我们对病毒发病机制的理解做出贡献，并为传染病管理提出新的方法。我将在一个杰出和特殊的研究环境中进行培训和研究。该环境将包括加州大学旧金山弗朗西斯科（UCSF）医学系、J.大卫Gladstone病毒学和免疫学研究所、旧金山弗朗西斯科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。这项研究计划利用了与HIV/HCV合并感染个体中HCV疾病治疗相关的偶然同步性。目前治疗HCV感染的标准是利巴韦林和免疫调节细胞因子干扰素-α（IFN-α）的联合治疗。临床研究表明，IFN-α治疗除了其预期的抗HCV的抗病毒作用外，还导致HIV-1病毒载量的显著降低。许多最近的体外研究表明，IFN-α处理强烈诱导抗病毒宿主因子APOBEC 3的表达。我们建议描述APOBEC 3活性对在UCSF医学中心或SFVAMC接受IFN-α治疗的HIV/HCV合并感染个体的现有广泛特征队列中观察到的HIV-1和HCV病毒血症抑制的贡献。本研究的目的是评估APOBEC 3活性作为新的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.