Long-term Effects of IDU, HIV, HCV and the Impact of HCV Cure on Immune Activation and Liver Fibrosis in Aging Women

项目总结/摘要 我们的总体目标是确定慢性HIV/HCV合并感染的长期后果， 注射药物使用（IDU）以及HCV治愈对肝纤维化和免疫激活关系的影响/ 生殖老化的艾滋病毒感染妇女的失调。肝脏疾病加速肝纤维化是一个主要的 HIV/HCV合并感染成人的死亡原因。整体免疫激活可能部分解释这种加速肝脏 纤维化随着不含干扰素的直接作用抗病毒药物（DAA）的出现， 疾病是预料之中的。目前尚不清楚HCV治愈后，HIV相关的免疫功能障碍是否会影响肝纤维化 或者残余肝损伤是否影响生育老化的HIV/HCV合并感染妇女的免疫恢复。雌激素 消耗与增加的免疫功能障碍和代谢紊乱，包括内脏肥胖， 可能会影响肝纤维化HCV感染对HIV和HCV的免疫发病机制有重要影响 疾病我们的研究表明，合并感染肝病的妇女与合并感染肝病的妇女相比， 肝脏疾病，增加了活化的CD 4 + T细胞，以及免疫调节和成熟的变化， 免疫稳态的关键途径，包括调节性（Treg）、衰老、效应记忆和效应T细胞 细胞合并感染的妇女也有较高水平的转化生长因子-β（TGF-β），一种免疫抑制因子， 对Treg分化至关重要的细胞因子和肝脏炎症和纤维化的重要调节因子，以及IL- 7，其促进HIV持续存在，刺激HIV复制和HIV储库，并促进纤维形成， 与HIV单一感染的女性相比。我们的中心假设是，在HCV治愈后，HIV/HCV- 合并感染的妇女，谁是老龄化，将有受损的肝纤维化消退，因为艾滋病毒- 相关免疫失调和代谢紊乱风险增加，包括肝脏 脂肪变性（或脂肪肝）。具体目标是：（1）纵向考察 HIV和绝经对老年HIV/HCV合并感染女性HCV治愈后肝纤维化的影响，以及（2）确定 在HIV/HCV合并感染的女性中，肝纤维化影响HCV治愈后的免疫激活和失调HCV- 单一感染者、HIV单一感染者和未感染者作为对照。我们计划使用药物， 绝经、代谢和肝纤维化数据，以及来自妇女跨部门艾滋病毒研究所的生物储存库样本。 学习（WIHS），以实现我们的目标。最先进的临床和实验室技术将评估肝脏 纤维化和脂肪变性的严重程度和基因特征表达，以阐明免疫激活的途径 和调节异常同时用细胞表型和可溶性生物标志物评估。WIHS 提供了一个独特的机会，梳理出艾滋病毒，丙型肝炎病毒，肝损伤和雌激素的复杂贡献， 女性免疫标记物的消耗。这项研究将帮助我们了解雌激素是否 如果残余肝损伤影响HIV相关免疫功能， 激活/失调。这将有助于为肝纤维化的预防和治疗提供信息。

Project Summary/Abstract Our overall goal is to determine the long-term consequences of chronic HIV/HCV coinfection as a result of injection drug use (IDU) and the impact of HCV cure on the relationship of liver fibrosis and immune activation/ dysregulation in reproductively aging HIV-infected women. Liver disease with accelerated liver fibrosis is a major cause of death in HIV/HCV coinfected adults. Global immune activation may partly explain this accelerated liver fibrosis. With the advent of interferon-free direct-acting antiviral agents (DAA), a decrease in the burden of liver disease is expected. It is unknown if, after HCV cure, HIV-associated immune dysfunction impacts liver fibrosis or if residual liver injury affects immune recovery in reproductively aging HIV/HCV-coinfected women. Estrogen depletion is associated with increased immune dysfunction and metabolic disruptions, including visceral obesity, which could impact liver fibrosis. HCV infection has a major impact on immunopathogenesis of HIV and HCV disease. Our studies show that coinfected women with liver disease as compared to coinfected women without liver disease, have increased activated CD4+ T cells, and changes in immune regulatory and maturational pathways critical for immune homeostasis, including regulatory (Treg), senescent, effector memory and effector T cells. Coinfected women also have higher levels of transforming growth factor-β (TGF-β), an immunosuppressive cytokine critical for Treg differentiation and an important regulator of liver inflammation and fibrosis, as well as IL- 7, which promotes HIV persistence, stimulates HIV replication and HIV reservoirs, and promotes fibrogenesis, compared to HIV-monoinfected women. Our central hypotheses are that after HCV cure, HIV/HCV- coinfected women, who are aging, will have impaired liver fibrosis regression, because of HIV- associated immune dysregulation and increased risk of metabolic perturbations including hepatic steatosis (or fatty liver). The specific aims are to: (1) Longitudinally examine the short and long-term effects of HIV and menopause on liver fibrosis after HCV cure in aging HIV/HCV-coinfected women and (2) Determine if liver fibrosis impacts immune activation and dysregulation after HCV cure in HIV/HCV-coinfected women. HCV- monoinfected, HIV-monoinfected and uninfected women will serve as controls. We plan to use medication, menopause, metabolic, and liver fibrosis data, and biorepository samples from the Women's Interagency HIV Study (WIHS), to accomplish our aims. State- of- the- art clinical and laboratory technologies will evaluate liver fibrosis and steatosis severity and gene-signature expression to elucidate pathways of immune activation and dysregulation assessed simultaneously with cellular phenotypic and soluble biomarkers. The WIHS provides a unique opportunity to tease out the complex contributions of HIV, HCV, liver injury and estrogen depletion on immunologic markers in women. The proposed studies will help us understand if estrogen depletion blunts recovery of liver injury after HCV cure and if residual liver injury affects HIV-associated immune activation/dysregulation. This will help inform strategies for prevention and treatment of liver fibrosis.