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：
9928694
负责人：
Shyamasundaran Kottilil
金额：
$ 7.67万
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/9928694
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 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.

抽象的据估计，有 300 万美国人患有慢性丙型肝炎 (HCV) 感染，其中高达 25% 患有慢性丙型肝炎 (HCV) 感染艾滋病毒。在新增 HCV 感染中，80% 发生在注射吸毒者 (PWID) 和成功吸毒者中为了打破这一流行病，需要针对这一核心群体制定治疗策略。直接作用抗病毒药物（DAA）是治疗 HCV 的新的非免疫疗法，并且可有效治疗 HIV 合并感染的 HCV；仍然与同时感染的个体相比，合并感染的个体肝纤维化进展更快，临床结果更差 HCV单一感染者。感染艾滋病毒的吸毒者的再感染率和肝病率显着更高即使在实现持续病毒学应答（SVR）后疾病仍会进展。调查长期的情况至关重要 SVR 在这些高危人群中的长期持续性，以确定导致 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 阳性吸毒者）巴尔的摩和哥伦比亚特区。我们发现，在通过 DAA 治疗实现 SVR 的患者中，HCV 特异性与 HCV 复发的患者相比，T 细胞免疫力得以恢复。我们正在寻求识别免疫成功治疗反应的相关性，特别是在高危人群中，目的是识别持续存在的病毒特异性免疫恢复的缺陷可能会妨碍 SVR 的持久性。在本提案中，我们将寻求 1) 研究 SVR 后肝脏疾病的改善情况以及 HIV/HCV 合并患者 SVR 后 HCV 再次感染率目前有或没有注射吸毒的感染患者 2) 探讨 HIV/HCV 双重感染的影响和目前注射药物对 HCV 特异性外周 CD4 和 CD8 T 细胞恢复和维持的影响 DAA 治疗后的反应以及 3) 表征 SVR 后肝脏免疫缺陷的持续存在 HIV/HCV合并感染的高危患者群体。通过这些具体目标，我们将阐明免疫导致 HIV/HCV 合并感染吸毒者再次感染的机制和因素。我们假设基于 DAA 根除丙型肝炎病毒将导致病毒特异性适应性免疫的增强，而这种免疫的缺乏可能是与 HIV/HCV 合并感染患者和当前吸毒者的不良后果相关。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物用于对不同淋巴细胞进行免疫表型分析的激活、传统流式细胞术和新型质谱流式细胞术外周人群和肝脏以及肝脏转录组测序，以量化 HCV 特异性免疫这些病人。我们的建议将为艾滋病毒/丙型肝炎病毒共存中的丙型肝炎病毒保护性免疫提供宝贵的见解。受感染的吸毒者，其再次感染和疾病进展的风险最高，并且是 HCV 的核心流行性。这将帮助我们识别可能需要额外干预的患者，并为制定针对感染艾滋病毒的注射吸毒者的创新预防策略，使我们能够破坏正在进行的丙肝病毒流行。