The Progression of Hepatitis C Among IDUs with HIV

描述（由申请人提供）：丙型肝炎病毒（HCV）感染引起的肝脏疾病是HIV感染者死亡的主要原因，在注射吸毒者（IDUs）中尤为重要。一些辅助因素恶化了HCV的进展，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，因此迄今为止，证明它们对肝脏疾病进展的独立贡献一直具有挑战性。该提案旨在研究HCV感染的IDUs中肝脏疾病进展的作用和机制，使用临床和实验室中的创新和补充工具。在第一个目标中，HIV对肝脏老化的影响将使用HIV感染者和未感染者队列中肝脏硬度的结构化纵向测量来研究，特别是抑制性HAART对纤维化进展率的影响。计划进行巢式机制研究，以了解HIV如何促进肝脏老化。第二个目标，重点是HCV复制，利用组织成像和标本收集的进展，研究单个肝细胞从存档的HCV感染的人类活检。在没有人HCV感染的代表性模型的情况下，将在同一个人中比较HCV感染肝细胞的分子特征与未感染肝细胞的分子特征，以确定HCV控制的潜在治疗靶点。第三个目标是集中在理解HCV感染从急性感染期间的治疗反应性向慢性感染期间的治疗抗性转变的背景下的HCV复制，扩展了IL 28 B基因位点强烈预测慢性感染中的治疗反应性的观察。在急性感染和早期慢性感染期间，将对具有有利和不利的IL28B基因型的人进行随访，并对外周血单核细胞和肝组织中的免疫活化和耐受性进行结构化测量，以靶向治疗抗性的潜在机制。拟议的研究将确定HCV感染的注射吸毒者肝脏疾病进展的关键途径。一项成功的提案的总体长期公共卫生影响是：a）减缓注射吸毒者肝脏疾病的进展和B）确定HCV控制的相关分子靶点。

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.