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

摘要 据估计，有300万美国人患有慢性丙型肝炎(HCV)，其中高达25%的人患有慢性丙型肝炎。 感染了艾滋病毒。在新的丙型肝炎病毒感染中，80%发生在注射毒品(PWID)并成功 需要针对这一核心群体的治疗策略才能打破这一流行病。直接作用抗病毒药物(DAA) 是治疗丙型肝炎病毒的新的非免疫疗法，在治疗丙型肝炎病毒和艾滋病毒合并感染方面是有效的； 合并感染的个体肝纤维化进展更快，临床结果更差 丙型肝炎病毒单一感染者。有HIV感染的PWID患者的再感染率和肝脏明显更高 即使在实现持续的病毒学应答(SVR)后，疾病仍在发展。关键是要调查长期的- SVR在这些高危人群中的长期持久性，以确定导致丙型肝炎的可能因素 复发。我们小组一直在研究丙型肝炎病毒治疗的反应(包括HIV阳性的PWID患者) 巴尔的摩和哥伦比亚特区。我们发现，在使用DAA治疗实现SVR的患者中，丙型肝炎病毒特异性 与丙型肝炎病毒复发者相比，T细胞免疫功能恢复。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，与确定持久的目标的相关性 病毒特异性免疫恢复中的缺陷，可能会阻碍SVR的持久性。在本提案中，我们将寻求1) 探讨人类免疫缺陷病毒/丙型肝炎病毒感染者SVR后肝病发生率和再感染率的改善情况 有或没有目前注射吸毒的感染者2)探讨艾滋病毒/丙型肝炎病毒混合感染的影响和 当前注射用药对丙型肝炎病毒特异性外周血中CD4和CD8T细胞恢复和维持的影响 DAA治疗后的反应和3)SVR后肝免疫缺陷的持续性 HIV/丙型肝炎合并感染的高危人群。通过这些特定的目标，我们将阐明免疫 HIV/丙型肝炎合并PWID患者再次感染的机制和因素我们假设基于DAA的 根除丙型肝炎病毒将导致病毒特异性获得性免疫的增强，这种免疫缺乏可能是 与艾滋病毒/丙型肝炎病毒混合感染患者的不良结局和目前的PWID有关。我们将采用标准 和新的研究技术，包括测量炎症和免疫的可溶性和细胞标记物 活化、常规流式细胞术和新型质量细胞术用于多种淋巴细胞免疫表型的研究 外周和肝脏中的群体和肝脏转录组测序以量化丙型肝炎病毒特异性免疫 这些病人。我们的建议将为人类免疫缺陷病毒/丙型肝炎病毒的保护性免疫提供有价值的见解。 受感染的PWID是再感染和疾病进展的最高风险，并且是丙型肝炎病毒的核心 流行病。这将帮助我们确定可能需要额外干预的患者，并为 针对艾滋病毒感染的PWID制定创新的预防战略，使我们能够扰乱正在进行的 丙型肝炎病毒流行。

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.