HIV, Kupffer Cells, and HCV-related Liver Fibrosis

描述（由申请人提供）：病毒性肝炎引起的肝脏疾病目前是艾滋病毒感染者死亡的主要原因，主要是慢性病毒性肝炎。该建议旨在确定HIV-HCV合并感染者中具有进展性肝病风险的分子靶点，这些靶点可用于治疗。HIV促进慢性病毒性肝炎患者肝纤维化的机制至少有两种高度可信的机制，这些机制集中在肝巨噬细胞（库普弗细胞）上。有初步数据表明，HIV感染库普弗细胞，这是体内最大的巨噬细胞储存库。虽然HIV感染这些细胞的程度和最终后果尚不清楚，但Kupffer细胞通过改变信号通路控制炎症/纤维化的作用提供了致病联系。此外，最近的研究表明，肠道组织的HIV感染可显著增强细菌产物（如脂多糖）通过门静脉循环进入肝脏的易位。由于Kupffer细胞主要负责清除这些产物，并且由于实验诱导的微生物易位增强了肝纤维化，因此HIV也可以通过这种机制通过Kupffer细胞促进肝纤维化。本研究的目的是通过关注HIV感染和HIV相关微生物易位对Kupffer细胞的影响来扩展这些观察结果。最初的调查将利用从一个具有良好特征的艾滋病毒感染者库中储存的肝活检，重点是使用免疫组织学和分子方法确定库普弗细胞艾滋病毒感染的程度。由于已知的介导HIV感染的辅助受体CCR5在实验性肝病的发展中发挥作用，后续的研究将使用分离的人类Kupffer细胞来鉴定Kupffer细胞上允许HIV感染的关键趋化因子辅助受体。最后，我们将进一步开发离体Kupffer细胞模型，研究脂多糖诱导和HIV感染时的纤维化信号模式，即tgf - β和tnf - α。拟议的研究将确定HIV-HCV合并感染中肝脏疾病的基本机制，研究人员将为合并感染者开发新的治疗方法。

DESCRIPTION (provided by applicant): Liver disease caused by viral hepatitis is now a leading cause of death in HIV-infected persons, mostly due to chronic viral hepatitis. This proposal is conceived to identify molecular targets in HIV-HCV co-infected persons at risk for progressive liver disease that can be exploited therapeutically. There are at least two highly plausible mechanisms through which HIV could promote liver fibrosis in a person with ongoing chronic viral hepatitis that focus on the hepatic macrophage (Kupffer cell). There are preliminary data that show that HIV infects Kupffer cells, the largest reservoir of resident tissue macrophages in the body. While the extent and ultimate consequence of HIV infection of these cells is unknown, the Kupffer cell's role governing inflammation/fibrosis via altered signaling pathways provides a pathogenic link. In addition, HIV infection of intestinal tissues has recently been shown to markedly enhance the translocation of bacterial products (e.g. lipopolysaccharide) through portal circulation to the liver. Since Kupffer cells are chiefly responsible for the clearance of these products and since experimentally induced microbial translocation enhances liver fibrosis, HIV also could promote liver fibrosis via Kupffer cells through this mechanism. The goal of this investigation is to extend these observations by focusing on the effect of HIV infection and HIV-related microbial translocation on Kupffer cells. Initial investigations will utilize stored liver biopsies from a well-characterized repository of HIV-infected persons, focusing on defining the extent of HIV infection of Kupffer cells using immunohistologic and molecular methods. Since CCR5, a known coreceptor mediating HIV infection, plays a role in the development of experimental liver disease, subsequent studies will use isolated human Kupffer cells to identify key chemokine coreceptors on Kupffer cells that permit HIV infection. Finally, the ex vivo Kupffer cell model will be further developed to study fibrogenic signaling patterns, i.e. TGF-beta and TNF-alpha, upon lipopolysaccharide induction and HIV infection. The proposed studies will define essential mechanisms of liver disease in HIV-HCV co-infection, and the investigators will develop insights into novel therapeutics for co-infected persons.