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

含有逆转录酶抑制剂(RTI)的联合抗逆转录病毒疗法(CART)只能减弱 艾滋病毒和乙肝病毒复制，对晚期肝病的治疗效果不大，这是导致 艾滋病毒感染者的发病率和死亡率。乙肝病毒诱导肝损伤的可能机制 目前尚不清楚HIV合并感染的发病机制和加速这一过程的机制 这在很大程度上是因为缺乏小动物模型。我们最近开发了新的人性化小鼠模型，携带 自体人类肝脏和免疫系统细胞，支持病毒性肝炎感染(乙肝/丙型肝炎)，艾滋病毒联合 感染和相关的肝病。炎症相关巨噬细胞主要来源于 循环中的单核细胞，是许多肝病炎症环境的主要成分； 然而，人们对它们在肝脏发病机制中的作用知之甚少。巨噬细胞被广泛地分类为M1 激活，促进Th1相关的抗病毒反应，以及M2样激活，削弱Th1 回应和促进组织病理学。我们最近发现慢性乙肝病毒/丙型肝炎病毒诱导的肝脏 人源化小鼠和人类的炎症与高水平的M2样渗透有关 巨噬细胞定位于纤维化区和肿瘤区。类似的发现也被报道在其他 炎症性疾病。HIV感染还导致两者M2样巨噬细胞激活增加 人性化的老鼠和人类。我们的中心假设是HIV加速了乙肝病毒/HIV共同感染的肝脏疾病。 感染通过加重肝脏中类M2巨噬细胞的病程。这项提议利用了一部小说 人源化小鼠模型，巨噬细胞-肝星状细胞共培养，以解决关键的知识差距 巨噬细胞活化在乙肝病毒/艾滋病合并感染及相关肝病中的作用为了澄清 巨噬细胞激活在乙肝病毒/艾滋病病毒混合感染和相关肝脏发病机制中的作用，特异性目标1将 探讨乙型肝炎病毒/艾滋病病毒混合感染及联合抗病毒治疗对单核/巨噬细胞的影响 人源化小鼠模型中的激活和肝病进展。具体目标2将是调查 巨噬细胞调节肝星状细胞活化及相关肝脏的分子基础 应用巨噬细胞-肝星状细胞共培养模型和人源化方法研究HBV/HIV混合感染中的肝纤维化 老鼠。这项工作将阐明巨噬细胞在乙肝病毒/艾滋病病毒混合感染和相关肝脏中的作用。 并导致针对炎症性肝病的新的治疗策略。

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.