Role of macrophage activation in HBV/HIV co-infection-induced liver disease

巨噬细胞激活在 HBV/HIV 合并感染引起的肝病中的作用

• 批准号: 9453233
• 负责人: Moses Turkle Bility
• 金额: $ 38.78万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-07 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9453233
• 关键词: AIDS/HIV problem; Address; Anabolism; Animal Model; Antiviral Response; Attenuated; Autologous; Cell Culture Techniques; Cells; Chronic; Clinical Investigator; Coculture Techniques; Collaborations; Coupled; Development; Disease; Disease Progression; Fibrosis; HIV; HIV Infections; HIV/HCV; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis B; Hepatitis C; Hepatitis C co-infection; Human; Immune; Immune response; Immune system; Impairment; Individual; Infection; Inflammation; Inflammatory; Knowledge; Lead; Liver; Liver diseases; Macrophage Activation; Malignant Neoplasms; Mediating; Modeling; Molecular; Morbidity - disease rate; NIH Program Announcements; Neoplasms; Pathogenesis; Pathology; Pathway interactions; Persons; Play; Polyamines; Process; Proline; Reporting; Reverse Transcriptase Inhibitors; Role; Therapeutic Effect; Tissues; Tropism; Viral; Viral hepatitis; Virus; Work; antiretroviral therapy; arginase; co-infection; humanized mouse; in vivo; inflammatory milieu; liver inflammation; macrophage; monocyte; mortality; mouse model; multidisciplinary; neoplastic; neurocognitive disorder; novel; novel therapeutics; response; standard of care

Combination antiretroviral therapy (cART) containing reverse transcriptase inhibitors (RTIs) can only attenuate HIV and HBV replication, and has marginal therapeutic effect on advanced liver diseases, a leading cause of morbidity and mortality in HIV-infected persons. The underlying mechanisms by which HBV-induced liver pathogenesis, and mechanisms by which HIV co-infection accelerate that process remain unknown due in large part to the lack of small animal models. We recently developed novel humanized mouse models carrying autologous human liver and immune system cells, which support viral hepatitis infections (HBV/HCV), HIV co- infections and associated liver diseases. Inflammation associated macrophages are mainly derived from circulating monocytes and represent a major component of the inflammatory milieu in many liver diseases; however, very little is known about their role in liver pathogenesis. Macrophages are broadly classified as M1 activated, which promote the Th1 associated anti-viral response, and M2-like activated which impair Th1 response and promote tissue pathology. We recently showed that chronic HBV/HCV-induced liver inflammation in both humanized mice and humans is associated with high levels of infiltrating M2-like macrophages which localized to fibrotic and neoplastic regions. Similar findings have been reported with other inflammatory diseases. HIV infection also results in increased M2-like macrophage activation in both humanized mice and humans. Our central hypothesis is that HIV accelerates liver disease in HBV/HIV co- infections by exacerbating M2-like macrophage pathogenesis in the liver. This proposal utilizes a novel humanized mouse model, and macrophage-hepatic stellate cell co-culture to address critical knowledge gaps on the role of macrophage activation in HBV/HIV co-infection and associated liver diseases. To elucidate the role of macrophage activation in HBV/HIV co-infection and associated liver pathogenesis, Specific Aim 1 will be to delineate the effect of HBV/HIV co-infection and associated anti-viral therapy on monocyte/macrophage activation and liver disease progression in the humanized mouse model. Specific Aim 2 will be to investigate the molecular basis by which macrophages modulate hepatic stellate cell activation and associated liver fibrogenesis in HBV/HIV co-infection using macrophage-hepatic stellate cell co-culture models and humanized mice. This work will elucidate the role of macrophages in HBV/HIV co-infection and associated liver pathogenesis, and lead to novel therapeutic strategies against inflammatory liver diseases.

含有逆转录酶抑制剂（RTIs）的联合抗逆转录病毒治疗（cART）只能减弱 HIV和HBV复制，对晚期肝病的治疗效果甚微，晚期肝病是导致肝硬化的主要原因。 艾滋病毒感染者的发病率和死亡率。HBV诱导肝细胞凋亡的机制 发病机制，以及艾滋病毒合并感染加速这一过程的机制仍然未知， 主要原因是缺乏小动物模型。我们最近开发了新的人源化小鼠模型， 自体人类肝脏和免疫系统细胞，支持病毒性肝炎感染（HBV/HCV），HIV共 感染和相关的肝脏疾病。炎症相关巨噬细胞主要来源于 循环单核细胞并代表许多肝脏疾病中炎性环境的主要成分; 然而，关于它们在肝脏发病机制中作用知之甚少。宏观经济学大致分类为M1 活化的，其促进Th 1相关的抗病毒应答，和M2样活化的，其损害Th 1 反应和促进组织病理学。我们最近发现，慢性HBV/HCV诱导的肝脏 人源化小鼠和人类的炎症都与高水平的浸润性M2样 巨噬细胞定位于纤维化和肿瘤区域。类似的发现也报告了其他 炎症性疾病。HIV感染还导致两种细胞中M2样巨噬细胞活化增加， 人源化小鼠和人。我们的中心假设是，HIV加速了HBV/HIV共感染者的肝脏疾病。 通过加重肝脏中的M2样巨噬细胞发病机制来治疗感染。该提案利用了一种新颖的 人源化小鼠模型和巨噬细胞-肝星状细胞共培养，以解决关键的知识缺口 巨噬细胞活化在HBV/HIV合并感染和相关肝病中的作用。阐明本 巨噬细胞活化在HBV/HIV合并感染和相关肝脏发病机制中的作用，特异性目的1将 描述HBV/HIV合并感染和相关抗病毒治疗对单核细胞/巨噬细胞的影响 活化和肝病进展。具体目标2将调查 巨噬细胞调节肝星状细胞活化及相关肝脏的分子基础 使用巨噬细胞-肝星状细胞共培养模型和人源化在HBV/HIV共感染中的纤维化 小鼠这项工作将阐明巨噬细胞在HBV/HIV合并感染和相关肝脏中的作用 发病机制，并导致针对炎症性肝病的新的治疗策略。