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

IDU、HIV、HCV 的长期影响以及 HCV 治愈对老年女性免疫激活和肝纤维化的影响

• 批准号: 9355485
• 负责人: Andrea A.Z. Kovacs
• 金额: $ 73.14万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355485
• 关键词: Acceleration; Adult; Affect; Age; Aging; Alcohol consumption; Antiviral Agents; Biological Markers; CD4 Positive T Lymphocytes; Cause of Death; Central obesity; Chronic; Clinical; Complex; Critical Pathways; DNA; Data; Disease; Dyslipidemias; Estrogens; Ethnic Origin; Fatty Liver; Fibrosis; Gene Expression Profile; Goals; HIV; HIV Infections; HIV/HCV; Hepatitis C; Hepatitis C co-infection; Homeostasis; Immune; Immune System Diseases; Immune System and Related Disorders; Immunity; Immunologic Markers; Immunosuppressive Agents; Impairment; Infection; Insulin Resistance; Interferons; Interleukin-7; Liver Fibrosis; Liver diseases; Long-Term Effects; Measurement; Memory; Menopause; Metabolic; Ovarian; Pathway interactions; Pharmaceutical Preparations; Phenotype; Prevention strategy; Production; RNA; Race; Recording of previous events; Recovery; Regulation; Regulatory T-Lymphocyte; Research; Research Infrastructure; Residual state; Risk; Sampling; Severities; Signal Transduction; T-Lymphocyte; Transforming Growth Factors; Woman; Women’s Interagency HIV Study; Work; age effect; biobank; cytokine; design; elastography; exhaustion; fibrogenesis; genetic signature; immune activation; injection drug use; laboratory equipment; liver inflammation; liver injury; mullerian-inhibiting hormone; novel marker; optimism; reproductive; senescence

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.

项目摘要/摘要 我们的总体目标是确定慢性艾滋病毒/丙型肝炎合并感染的长期后果 注射用药及丙型肝炎病毒治愈对肝纤维化和免疫激活关系的影响 生殖性衰老的艾滋病毒感染妇女的调节失调。伴有加速肝纤维化的肝病是一种 艾滋病毒/丙型肝炎混合感染成人的死因。全球免疫激活可能在一定程度上解释了这种肝脏加速 纤维化症。随着不含干扰素的直接作用抗病毒药物(DAA)的问世，肝脏负担减轻 疾病是预料之中的。丙型肝炎病毒治愈后，艾滋病毒相关免疫功能障碍是否会影响肝纤维化尚不清楚。 或者残留的肝脏损伤是否会影响生殖性衰老的艾滋病毒/丙型肝炎病毒感染女性的免疫恢复。雌激素 衰竭与免疫功能障碍和代谢紊乱的增加有关，包括内脏肥胖， 这可能会影响肝纤维化。丙型肝炎病毒感染对人类免疫缺陷病毒和丙型肝炎病毒的免疫发病机制有重要影响 疾病。我们的研究表明，合并感染肝病的女性与没有合并感染的女性相比 肝病，有活化的CD4+T细胞增多，免疫调节和成熟的变化 免疫稳态的关键途径，包括调节(Treg)、衰老、效应器记忆和效应器T 细胞。合并感染的女性也有较高水平的转化生长因子-β(转化生长因子-β)，这是一种免疫抑制剂 Treg分化的关键细胞因子和肝脏炎症和纤维化的重要调节因子，以及IL-1。 7，它促进艾滋病毒的持久性，刺激艾滋病毒复制和艾滋病毒贮存库，并促进纤维化， 与单一感染艾滋病毒的女性相比。我们的中心假设是，在丙型肝炎治愈后，艾滋病毒/丙型肝炎病毒- 随着年龄的增长，合并感染的女性将会出现肝纤维化的受损消退，因为艾滋病毒- 相关的免疫失调和包括肝脏在内的代谢紊乱风险增加 脂肪变性(或脂肪肝)。具体目标是：(1)纵向考察以下项目的短期和长期影响 老年艾滋病毒/丙型肝炎合并感染妇女丙型肝炎治愈后HIV和绝经对肝纤维化的影响及(2)确定 肝纤维化影响艾滋病毒/丙型肝炎合并感染妇女丙型肝炎治愈后的免疫激活和调节失调。丙型肝炎病毒- 单一感染、艾滋病毒单一感染和未感染的妇女将作为对照。我们计划使用药物治疗， 更年期、代谢和肝纤维化数据，以及妇女机构间艾滋病毒生物信息库样本 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信号表达以阐明免疫激活的途径 同时用细胞表型和可溶性生物标记物评估细胞调节失调。WIHS 提供了一个独特的机会来梳理艾滋病毒、丙型肝炎病毒、肝脏损伤和雌激素的复杂作用 女性免疫标记物的耗竭。拟议中的研究将帮助我们了解雌激素是否 丙型肝炎病毒治愈后肝损伤的恢复和残留的肝损伤是否影响HIV相关免疫 激活/失调。这将有助于制定预防和治疗肝纤维化的策略。