The Progression of Hepatitis C Among IDUs with HIV

描述（由申请人提供）：由丙型肝炎病毒（HCV）感染引起的肝脏疾病是艾滋病毒感染者死亡的主要原因，在注射吸毒者（IDUs）中尤为重要。几个辅助因素加重HCV进展，包括HIV、年龄和HCV复制增强。由于HIV和衰老相互影响并影响HCV复制，证明它们对肝脏疾病进展的独立贡献至今仍是一个挑战。本研究的目的是利用临床和实验室的创新和互补工具，研究丙型肝炎病毒感染注射吸毒者肝脏疾病进展的作用和机制。在第一个目标中，HIV对肝脏衰老的影响将在HIV感染者和未感染者队列中使用结构化的肝脏硬度纵向测量来研究，特别是抑制性HAART对纤维化进展率的影响。巢式机制研究计划了解艾滋病毒如何促进肝脏老化。第二个目标侧重于HCV复制，利用组织成像和标本收集的进步来研究HCV感染人类活组织的单个肝细胞。缺乏人类HCV感染的代表性模型，HCV感染肝细胞的分子特征将在同一人体内与未感染肝细胞进行比较，以确定HCV控制的潜在治疗靶点。第三个目标集中在了解HCV感染从急性感染期间的治疗反应性到慢性感染期间的治疗抵抗性转变背景下的HCV复制，扩展IL28B基因位点强烈预测慢性感染治疗反应性的观察结果。在急性感染和早期慢性感染期间，将对具有有利和不利IL28B基因型的人进行随访，对其外周血单个核细胞和肝组织的免疫激活和耐受性进行结构化测量，以确定治疗耐药性的目标机制。拟议的研究将确定丙型肝炎病毒感染注射吸毒者肝脏疾病进展的关键途径。成功的建议对公共卫生的总体长期影响是：a)减轻注射吸毒者肝脏疾病的进展；b)确定控制丙型肝炎病毒的相关分子靶点。

DESCRIPTION (provided by applicant): Liver disease caused by infection with Hepatitis C Virus (HCV) is a leading cause of death in HIV-infected persons, and is of particular importance among injection drug users (IDUs). Several cofactors worsen HCV progression, including HIV, age, and enhanced HCV replication. Since HIV and aging impact on each other and on HCV replication, demonstrating their independent contributions to liver disease progression has been challenging up till now. This proposal is conceived to investigate the role and mechanism(s) underlying liver disease progression in HCV-infected IDUs using innovative and complementary tools in the clinic and lab. In the first aim, the effect of HIV on aging in the liver will be studed using structured longitudinal measurements of liver stiffness in a cohort of HIV-infected and - uninfected persons, and especially on the effect of suppressive HAART on fibrosis progression rates. Nested mechanistic studies are planned to understand how HIV contributes to the aging liver. The second aim, focused on HCV replication, leverages advances in tissue imaging and specimen collection to study single hepatocytes from archived HCV-infected human biopsies. Absent a representative model of human HCV infection, molecular signatures of HCV- infected hepatocytes will be compared within the same person to those of uninfected hepatocytes, identifying potential therapeutic targets for HCV control. The third aim is centered on understanding HCV replication in the context of the transition of HCV infection from treatment-responsive during acute infection to treatment-resistant during chronic infection, extending the observation that the IL28B gene locus strongly predicts treatment responsiveness in chronic infection. Persons with favorable and unfavorable IL28B genotypes will be followed during acute infection and early chronic infection with structured measurements of immune activation and tolerance in peripheral blood mononuclear cells and liver tissue to target mechanisms underlying treatment resistance. The proposed studies will define key pathways of liver disease progression in HCV-infected IDUs. The overall long-term public health impact of a successful proposal is to a) attenuate the progression of liver disease in IDUs and b) to identify relevant molecular targets for HCV control.