Mechanisms of Neutralizing Antibody Resistance in Chronic HCV and HIV Infection

描述（由申请人提供）：本次K08职业发展奖的研究目标是定义介导自身中和抗体（nAb）逃逸的丙型肝炎病毒（HCV）包膜突变的共享模式，测量这些突变的适应度成本，并定义在HCV感染期间诱导的编码广泛中和抗体的人类B细胞库。通过指导、结构化教学和实验室经验，K08职业发展奖是一个理想的机制，使Justin Bailey博士成为一名独立研究者，在HCV感染中进行广泛中和抗体反应的转化研究。候选人：贝利博士是约翰·霍普金斯医院传染病学奖学金培训的最后一年的内科医生。他于2007年通过医学科学家培训计划在约翰霍普金斯大学医学院获得医学博士和免疫学博士学位，并于2009年通过ABIM研究途径在马萨诸塞州总医院完成内科住院医师培训。他在感染性疾病研究期间与他的主要导师Stuart Ray博士一起研究丙型肝炎病毒（HCV）包膜进化。他的短期目标是识别和表征HCV nAb逃逸突变，定义广泛nAb反应的遗传特征，获得杂交瘤产生和深度测序的实践经验，并在生物信息学方法和B细胞免疫学方面进行教学培训。他的长期目标是成为一名独立的研究者，研究病毒进化和B细胞库进化的机制，从而导致广泛的nAb反应。环境:本提案中描述的调查将在约翰霍普金斯医院传染病科教授Stuart Ray博士和儿科教授James E. Crowe, Jr.的实验室进行，Stuart Ray博士是HCV病毒学、体液免疫和计算生物学方面的国际公认专家。范德比尔特大学医学中心的微生物学和免疫学专家，也是B细胞生物学和人类对病毒产生有效B细胞反应的分子基础方面的专家。两位导师都是各自领域的领军人物，资金雄厚，在指导年轻研究人员走向独立方面有着良好的记录。两位导师的实验室都有必要的设备来完成拟议的研究，相关的患者样本、抗体和其他试剂也很容易获得。研究：迫切需要一种针对丙型肝炎病毒（HCV）的疫苗，诱导有效的中和抗体反应可能是任何成功疫苗策略的基石。困难在于丙型肝炎病毒会大量复制

DESCRIPTION (provided by applicant): The research objectives of this K08 career development award are to to define shared patterns of hepatitis C virus (HCV) envelope mutation that mediate escape from autologous neutralizing antibody (nAb), to measure the fitness costs of those mutations, and to define the human B cell repertoire encoding broadly neutralizing antibodies induced during HCV infection. Through mentoring, structured didactics and laboratory experience, this K08 career development award is the ideal mechanism to allow Dr. Justin Bailey to become an independent investigator conducting translational research on broadly neutralizing antibody responses in HCV infection. Candidate: Dr. Bailey is a physician in his final year of fellowship training in Infectious Diseases at the Johns Hopkins Hospital. He earned an M.D. and Ph.D. in Immunology at the Johns Hopkins University School of Medicine through the Medical Scientist Training Program in 2007 and completed residency training in Internal Medicine at the Massachusetts General Hospital through the ABIM research pathway in 2009. He has spent the research years of his Infectious Diseases fellowship studying hepatitis C virus (HCV) envelope evolution with his primary mentor, Dr. Stuart Ray. His short term goals are to identify and characterize HCV nAb escape mutations, to define genetic characteristics of a broad nAb response, to gain practical experience in hybridoma generation and deep sequencing, and to pursue didactic training in bioinformatic methods and B cell immunology. His long term goal is to become an independent investigator studying the mechanisms by which viral evolution and evolution of the B cell repertoire can lead to a broad nAb response. Environment: The investigations described in this proposal will be performed in the laboratories of Dr Stuart Ray, a Professor in the Infectious Diseases Division at Johns Hopkins Hospital and an internationally- recognized expert in HCV virology, humoral immunity, and computational biology and Dr. James E. Crowe, Jr., a Professor of Pediatrics, Microbiology and Immunology at Vanderbilt University Medical Center and an expert in B cell biology and the molecular basis for the development of effective B cell responses to viruses in humans. Both mentors are leaders in their respective fields, are well-funded, and have a strong track record of mentoring young investigators to independence. Necessary equipment is available in the labs of both mentors for the completion of the proposed studies, and relevant patient samples, antibodies, and other reagents are readily available. Research: A vaccine against hepatitis C virus (HCV) is urgently needed, and induction of an effective neutralizing antibody response will likely be a keystone of any successful vaccine strategy. The difficulty lies in the fact that HCV replicates to high levels using an error-prone polymerase, leading to extensive world-wide genetic diversity of the virus and rapid viral evolution in infected individuals. Most antibodies induced during natural infection do not have broad enough specificity to neutralize diverse HCV isolates, and viral evolution can lead to escape from nAb responses in individuals who become infected. However, rare infected individuals develop broad nAb responses, and nAb escape mutations in some epitopes may convey significant fitness cost to the virus. The goal of this investigation is to define shared patterns of hepatitis C virus (HCV) envelope mutation that mediate escape from autologous neutralizing antibody (nAb), to measure the fitness costs of those mutations, and to define the human B cell repertoire encoding broadly neutralizing antibodies induced during HCV infection. A better understanding of these questions will facilitate HCV vaccine development by identifying immunogenic but fitness-constrained epitopes that might serve as vaccine antigens and also by defining genetic features of broadly nAb that should be induced by a vaccine against HCV. The research described in this proposal is novel, achievable within the award period, and of high potential significance. Through the research experience acquired through completion of this work, intensive mentoring, and structured didactics, this K08 career development award will allow the primary investigator, Dr. Justin Bailey, to become an independent investigator conducting translational research on broadly neutralizing antibody responses in HCV infection. Relevance The World Health Organization estimates there are 170 million persons with hepatitis C virus (HCV) infection worldwide, and in most countries, HCV infection is found in 1-2% of the general population. A vaccine to prevent or attenuate HCV infection is urgently needed, and stimulation of effective neutralizing antibody (nAb) responses will likely be a keystone of any successful vaccine strategy. Therefore, a better understanding of viral escape from nAb and development of broadly nAb responses should facilitate HCV vaccine development.