Immune correlates of long-term success with DAA therapy in HCV/HIV infected people who inject drugs

DAA 治疗 HCV/HIV 感染注射吸毒者长期成功的免疫相关性

基本信息

批准号：
9918287
负责人：
Shyamasundaran Kottilil
金额：
$ 36.5万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918287
关键词：
Address American Antiviral Agents Baltimore CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Caring Chronic Hepatitis C Clinical Cytometry Data Defect Development Disease Progression District of Columbia Effectiveness Epidemic Evaluation Flow Cytometry Goals HIV HIV Infections HIV Seropositivity HIV/HCV Hepatic Hepatitis C Hepatitis C Incidence Hepatitis C Prevalence Hepatitis C Therapy Hepatitis C Transmission Hepatitis C co-infection Hepatitis C virus High Prevalence Immune Immune System Diseases Immunity Immunophenotyping Impairment Individual Infection Inflammation Injecting drug user Interferons Interruption Intervention Investigation Knowledge Liver Liver Failure Liver Fibrosis Liver diseases Longitudinal Studies Lymphocyte Maintenance Malignant neoplasm of liver Measures Mediating Mission Morbidity - disease rate Natural History New Agents Opioid replacement therapy Outcome Patients Peripheral Pharmaceutical Preparations Plasma Population Prevention Prevention strategy RNA Recovery Recurrence Regimen Relapse Research Technics Retreatment Role Route T cell response T-Lymphocyte Treatment Effectiveness Viral Viral hepatitis Virus Work activation product adaptive immunity adverse outcome base co-infection cost design exhaustion high risk high risk population immune activation improved infection rate inflammatory marker injection drug use innovation insight interest intrahepatic medication-assisted treatment mortality novel opioid use prevent progenitor public health relevance response success therapeutic immunization therapeutic vaccine transcriptome sequencing transmission process treatment response treatment strategy virology

项目摘要

Abstract An estimated 3 million Americans have chronic Hepatitis C (HCV) infection, and of those, up to 25% are co- infected with HIV. Of the new HCV infections, 80% occur in people who inject drugs (PWID) and successful treatment strategies for this core group are required to break this epidemic. Directly acting antiviral agents (DAAs) are new non-immune based therapies to treat HCV and are effective in treating HCV with HIV co-infection; still individuals with co-infection have more rapid progression of hepatic fibrosis and worse clinical outcomes than those with HCV mono-infection. PWID with HIV infection have significantly higher rates of re-infection and liver disease progression even after achieving sustained virologic response (SVR). It is critical to investigate the long- term durability of SVR in these high-risk populations in order to identify probable factors that contribute to HCV recurrence. Our group has been studying HCV treatment responses (including HIV positive PWID patients) in Baltimore and District of Columbia. We showed that in patients achieving SVR with DAA therapy, HCV specific T cell immunity is recovered in contrast to those with relapse of HCV. We are seeking to identify immune correlates of successful treatment response, especially in high-risk groups, with the goal of identifying persistent defects in virus specific immune recovery that may hamper durability of SVR. In this proposal, we will seek to 1) investigate the improvement in liver disease with SVR and HCV re-infection rates post SVR in HIV/HCV co- infected patients with or without current injection drug use 2) explore the impact of HIV/HCV co-infection and current injection drug use on recovery and maintenance of HCV-specific peripheral CD4 and CD8 T- cell responses after DAA therapy and 3) characterize the persistence of hepatic immune defects after SVR in HIV/HCV co-infected high-risk patient groups. Through these specific aims, we will elucidate the immune mechanisms and factors that drive re-infection in HIV/HCV co-infected PWID. We hypothesize that DAA-based eradication of HCV will result in augmentation of virus specific adaptive immunity, the lack of which may be associated with adverse outcomes in HIV/HCV co-infected patients and current PWID. We will employ standard and novel research techniques, including measuring soluble and cellular markers of inflammation and immune activation, conventional flow cytometry and novel mass cytometry for immunophenotyping diverse lymphocyte populations in periphery and liver and hepatic transcriptome sequencing to quantify HCV-specific immunity in these patients. Our proposal will provide valuable insights in protective immunity against HCV in HIV/HCV co- infected PWID who are at highest risk of reinfection and disease progression and are at the core of HCV epidemic. This will help us identify patients that may require additional intervention, and pave the way for development of innovative preventive strategies targeting HIV infected PWID enabling us to disrupt the ongoing HCV epidemic.

抽象的估计有300万美国人患有慢性丙型肝炎（HCV）感染，其中高达25％是共同的感染艾滋病毒。在新的HCV感染中，注射药物（PWID）和成功的人中发生了80％该核心组的治疗策略需要打破这种流行病。直接起作用抗病毒药（DAAS）是治疗HCV的新型非免疫疗法，可有效治疗HIV共同感染的HCV；仍然共同感染的人比肝纤维化的进展更快，临床结果差。具有HCV单感染的人。艾滋病毒感染的PWID具有重新感染和肝脏的率明显更高即使达到持续的病毒学反应（SVR），疾病进展也是如此。研究长期至关重要在这些高风险人群中SVR的术语耐用性，以识别有助于HCV的可能因素复发。我们的小组一直在研究HCV治疗反应（包括HIV阳性PWID患者）巴尔的摩和哥伦比亚特区。我们表明，在使用DAA治疗的患者中，HCV特异性与HCV复发的人相比，T细胞免疫恢复了。我们正在寻求识别免疫力成功治疗反应的相关性，尤其是在高风险群体中，目的是确定持久性病毒特异性免疫恢复的缺陷可能会阻碍SVR的耐用性。在此提案中，我们将寻求1）调查HIV/HCV共同体SVR后SVR和HCV再感染率的肝病的改善感染有或没有当前注射药物使用的患者2）探索HIV/HCV共同感染的影响当前的注射药物用于恢复和维持HCV特异性外围CD4和CD8 T细胞的使用 DAA治疗后的反应和3）表征SVR后肝免疫缺陷的持久性 HIV/HCV共感染的高危患者组。通过这些特定目标，我们将阐明免疫促进HIV/HCV共感染的PWID的机制和因素。我们假设基于DAA 根除HCV将导致病毒特异性适应性免疫的增强，其中缺乏可能是与HIV/HCV共感染的患者和当前PWID的不良结局有关。我们将采用标准以及新颖的研究技术，包括测量炎症和免疫的可溶性和细胞标记激活，常规流式细胞术和新型质量细胞仪，用于免疫表型多样化的淋巴细胞外围和肝脏中的种群以及肝转录组测序，以量化HCV特异性免疫力这些患者。我们的建议将提供有价值的见解，以防止艾滋病毒/HCV共同进行HCV的保护性免疫。受感染的PWID是重新感染和疾病进展的最高风险，并且是HCV的核心流行性。这将帮助我们确定可能需要额外干预的患者，并为制定针对艾滋病毒感染的PWID的创新预防策略，使我们能够破坏正在进行的 HCV流行。