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现在是HIV感染者死亡的主要原因，主要是由于慢性病毒性肝炎。该建议旨在确定HIV-HCV合并感染者中具有进行性肝病风险的分子靶点，这些分子靶点可用于治疗。至少有两种高度合理的机制，通过这种机制，艾滋病毒可以促进慢性病毒性肝炎患者的肝纤维化，重点是肝巨噬细胞（枯否细胞）。有初步数据表明，艾滋病毒感染库普弗细胞，最大的水库居民组织巨噬细胞在体内。虽然HIV感染这些细胞的程度和最终后果尚不清楚，但库普弗细胞通过改变的信号通路控制炎症/纤维化的作用提供了致病联系。此外，最近已显示肠组织的HIV感染显著增强细菌产物（例如脂多糖）通过门静脉循环至肝脏的移位。由于枯否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也可以通过枯否细胞通过这种机制促进肝纤维化。本研究的目的是通过关注HIV感染和HIV相关微生物易位对枯否细胞的影响来扩展这些观察结果。初步调查将利用储存的肝活检从一个良好的特征库的艾滋病毒感染者，重点是确定的程度，艾滋病毒感染的库普弗细胞使用免疫组织学和分子方法。由于CCR 5是一种已知的介导HIV感染的辅助受体，在实验性肝病的发展中起作用，后续研究将使用分离的人库普弗细胞来鉴定库普弗细胞上允许HIV感染的关键趋化因子辅助受体。最后，将进一步开发离体枯否细胞模型，以研究脂多糖诱导和HIV感染后的纤维化信号传导模式，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.