Elucidating Mechanisms of Treatment Relapse for Interferon-Free HCV Therapy

阐明无干扰素 HCV 治疗复发的机制

• 批准号: 9012319
• 负责人: Eric G. Meissner
• 金额: $ 18.46万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9012319
• 关键词: Address; Affect; Aftercare; Antiviral Agents; Appointment; Bioinformatics; Blood Cells; Blood specimen; Caring; Characteristics; Chronic; Chronic Hepatitis C; Cirrhosis; Clinic; Clinical; Communicable Diseases; Data; Development; Disease Progression; Environment; Evolution; Fibrosis; Genetic; Goals; HIV; Health; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocyte; Immune; Immune response; Immunity; Immunology; In Vitro; Individual; Infection; Inflammation; Injectable; Integration Host Factors; Interferon Type I; Interferon Type II; Interferons; Investigation; Journals; Lead; Ligands; Liver; Lymphocyte; Measures; Medical; Mentors; Methods; Microbiology; Natural Immunity; Nature; Oral; Outcome; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Physicians; Primary carcinoma of the liver cells; Probability; Proteome; Proteomics; Publishing; Relapse; Research Personnel; Residual state; Role; Safety; Sampling; Scientist; Signal Transduction; South Carolina; Testing; Time; Tissues; Toll-like receptors; Training; Treatment Failure; Treatment outcome; United States; Universities; Viral Load result; Viral Proteins; Virus; Virus Diseases; Whole Blood; Work; adaptive immunity; base; career; clinical investigation; comparative efficacy; experience; genetic signature; immune activation; improved; individualized medicine; insight; intrahepatic; lipid metabolism; liquid chromatography mass spectrometry; liver biopsy; monocyte; mortality; multidisciplinary; pathogen; peripheral blood; predictive marker; prevent; relapse patients; relapse prediction; repository; response; restoration; standard of care; success; tool; treatment duration

 DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infects 170 million people worldwide, and is a leading cause of liver-related mortality due to development of cirrhosis and hepatocellular carcinoma. Treatment of chronic HCV infection is now possible with combinations of oral, directly acting antiviral agents (DAAs), which do not require exogenous injectable interferon (IFN) to achieve HCV eradication. Treatment failure with DAA therapy typically occurs due to HCV relapse after treatment, although mechanisms are poorly understood. Furthermore, the necessary duration of treatment required to achieve a sustained virologic response (SVR), synonymous with HCV eradication, differs between people, and may be influenced by host immunity. The goal of this project is to discover host immune correlates and mechanisms of treatment outcome during IFN-free DAA therapy for HCV. To accomplish this, the applicant will utilize clinical samples collected during therapy to assess differences between subjects who achieve SVR versus relapse in markers of (1) immune activation and interferon sensitivity in peripheral blood, (2) the liver proteome before and after treatment, with analysis using bioinformatics platforms, and (3) in vitro sensitivity of lymphocytes and monocytes during DAA therapy to exogenous immune stimulation, asking whether such stimulation at the end of treatment could prevent relapse. The applicant, Dr. Meissner, is a physician-scientist in the Division of Infectious Diseases at the Medical University of South Carolina, with a secondary appointment in the Department of Microbiology and Immunology. His long-term career goal is to become an independent investigator studying mechanisms of inter-individual immune variability in response to chronic viral infections, in order to better understand disease progression and differential response to therapies. To facilitate his transition to investigative independence, he is seeking to broaden the multidisciplinary nature of his investigations by developing expertise in tissue proteomics, in vitro study of immunity, and use of bioinformatic tools. The environment for the success of Dr. Meissner is provided by (1) a multi-disciplinary team with a track record of mentoring and expertise needed to support the project, (2) departmental and divisional support with protected time to develop a career as a physician scientist, (3) availability of a unique set f clinical samples collected during IFN-free therapy for chronic HCV infection, and (4) active clinical participation in an Infectious Diseases clinic providing care to patients infected with HC alone or co-infected with HCV and the human immunodeficiency virus (HIV). Identification of correlates and mechanisms of treatment relapse during DAA therapy for HCV infection will provide timely contributions to an active clinical field that is changing dynamically with new treatment options. This training will enable Dr. Meissner to achieve his long-term goal of becoming an independent investigator leading multidisciplinary efforts to study variability in the host response to chronic viral infections including HCV, HIV, and hepatitis B virus, with the aim of understanding and improving clinical outcomes.

 描述（由适用提供）：全球丙型肝炎病毒（HCV）感染1.7亿人，是由于肝硬化和肝细胞癌的发展而导致与实时死亡有关的主要原因。现在可以通过口服，直接作用抗病毒药（DAAS）的组合来治疗慢性HCV感染，这些抗病毒剂（DAAS）不需要外源注射干扰素（IFN）以实现HCV放疗。 DAA治疗的治疗衰竭通常是由于治疗后HCV继电器而发生的，尽管理解的机制知之甚少。此外，实现持续的病毒学反应（SVR）所需的必要治疗持续时间，与HCV辐射的合成，人之间有所不同，并且可能受到宿主免疫史的影响。该项目的目的是发现HCV无IFN DAA治疗期间的宿主免疫相关性和机制。为此，适用的将利用在治疗期间收集的临床样本来评估（（1）（1）（1）在（1）标记中实现SVR与继电器的受试者之间的差异，（1）外周血中的免疫活性和干扰敏感性，（（2）使用生物信息的疗法和（3）在体内（3）vaimities and（3）治疗前后的肝脏蛋白质组，并在（3）中进行分析。进行外源性免疫刺激，询问治疗结束时这种刺激是否可以防止退休。 申请人Meissner博士是南卡罗来纳州医科大学传染病科的身体科学家，并在微生物学和免疫学系任命。他的长期职业目标是成为一名独立研究者，研究对慢性病毒感染的响应，个人间免疫可变性的机制，以便更好地了解疾病进展和对疗法的差异反应。为了促进他向调查独立的过渡，他正在寻求 通过发展组织蛋白质组学，体外研究和使用生物信息学工具的专业知识来扩大他的研究的多学科性质。 （1）一个多学科的团队提供了Meissner博士成功的环境，该团队具有支持该项目所需的心理和专业知识的记录，（2）部门和分区支持，并提供了受保护的时间来发展作为物理科学家的职业，（3）在IFN无效的临床治疗期间收集的独特临床临床疗法和（4）的临床临床疗法，并（4单独感染HC或与HCV和人类免疫缺陷病毒（HIV）共感染患者。 在DAA治疗期间，HCV感染期间治疗继电器的对应关系和机制的鉴定将为主动临床领域提供及时的贡献，该领域正在通过新的治疗选择动态变化。这项培训将使Meissner博士实现自己的长期目标，即成为一名独立的研究者，领导多学科的努力，以研究宿主对慢性病毒感染的反应的变异性，包括HCV，HIV和乙型肝炎病毒，以理解和改善临床结果。