HIV-Associated Macrophage Alterations and Progressive Liver Disease

 描述（由申请人提供）： HIV合并感染加速了HCV和HBV相关肝病的进展，是一个主要的公共卫生问题。慢性炎症是慢性病毒性肝炎的标志，其特征在于炎性细胞群的浸润，包括活化的巨噬细胞，其也是HIV的重要储库。活化的肝巨噬细胞转化为M1/促炎或M2/促纤维化表型，可活化肝星状细胞，导致纤维化。可溶性CD 163（sCD 163）的循环水平，一个特征性的M2标志物，已与慢性HCV和HBV的纤维化密切相关。重要的是，在HIV感染中也观察到高水平的sCD 163。我们的初步数据表明，与HIV或HCV单独感染相比，HIV/HCV合并感染中sCD 163的增加显著更大，并且sCD 163水平与肝纤维化分期显著相关。我们还观察到，HIV/HCV合并感染中成功的抗逆转录病毒治疗显着降低了sCD 163水平。我们还表明，HIV和HCV在体外共同诱导M2表型。我们假设HIV直接和间接地导致促纤维化M2巨噬细胞的扩张，这反过来又加剧了病毒性肝炎背景下的肝纤维化。有趣的是，最近报道了表达表皮生长因子受体（EGFR）的巨噬细胞通过IL-6依赖性机制在促进肝细胞癌中起重要作用。由于IL-6可以诱导M2极化和HIV已被证明能增强感染细胞中的EGFR信号传导，我们进一步假设EGF信号传导介导HIV对促纤维化状态产生的贡献。我们建议通过以下目的进一步探讨这些假设：（1）确定慢性病毒性肝病患者和非慢性病毒性肝病患者中HIV感染与M2标志物的相关性。使用慢性HCV和HBV患者的肝组织，我们将评估每种疾病是否与HIV合并感染中增强的肝内M2表型相关。我们还将通过评价来自无肝病证据的HIV单感染者的肝组织并与正常肝组织进行比较，评估HIV单感染是否与M2肝脏特征相关。(2)进行机制研究，其目标是确定HIV如何促进促纤维化巨噬细胞极化的扩展。我们将使用RNA-Seq专门评估HIV对肝脏巨噬细胞的影响，并将通过进行抑制剂研究评估EGFR信号传导对HIV对巨噬细胞群体影响的贡献。我们还将评估艾滋病毒的促进纤维化使用星状细胞共培养。(3)评价抗逆转录病毒抑制HIV对肝巨噬细胞的影响。后者的研究将进行使用肝细针抽吸物从HIV/HCV合并感染的人开始接受ART。我们将测试的假设，成功的HIV抑制部分，但不完全逆转的影响，艾滋病毒的促纤维化巨噬细胞表型的改变。这些研究将有助于阐明巨噬细胞对HIV相关肝纤维化进展的贡献。

 DESCRIPTION (provided by applicant): HIV co-infection accelerates HCV- and HBV-related liver disease progression and represents a major public health problem. Chronic inflammation, the hallmark of chronic viral hepatitis, is characterized by infiltration of inflammatory cell populations, including activated macrophages, which are also important reservoirs for HIV. Activated hepatic macrophages polarize into M1/pro-inflammatory or M2/profibrotic phenotypes that can activate hepatic stellate cells, leading to fibrosis. Circulating levels of soluble CD163 (sCD163), a characteristic M2 marker, have been strongly associated with fibrosis in chronic HCV and HBV. Importantly, high levels of sCD163 are also observed in HIV infection. Our preliminary data demonstrate significantly greater increase of sCD163 in HIV/HCV co-infection compared to HIV or HCV alone and that sCD163 levels significantly correlate with liver fibrosis stage. We also observed that successful anti-retroviral therapy in HIV/HCV coinfection significantly decreased sCD163 levels. We have also shown that HIV and HCV together cooperatively induce the M2 phenotype in vitro. We hypothesize that HIV directly and indirectly contributes to the expansion of profibrotic M2 macrophages, which in turn exacerbate liver fibrosis in the setting of viral hepatitis. Intriguingl, macrophages expressing epidermal growth factor receptor (EGFR) have been recently reported to play an essential role in promoting hepatocellular carcinoma via IL-6 dependent mechanisms. Since IL-6 can induce M2 polarization and HIV has been shown to enhance EGFR signaling in infected cells, we further hypothesize that EGF signaling mediates HIV's contribution to generation of the profibrogenic state. We propose to further explore these hypotheses through the following aims: (1) Determine the association of HIV infection with M2 markers in patients with and without chronic viral liver disease. Using liver tissue from patients with chronic HCV and HBV, we will assess whether each condition is associated with enhanced intrahepatic M2 phenotype in HIV coinfection. We will also assess whether HIV monoinfection is associated with the M2 hepatic profile by evaluating liver tissue from HIV monoinfected persons without evidence of liver disease and comparing to normal liver tissue. (2) Perform mechanistic studies whose goal is to define how HIV promotes expansion of profibrotic macrophage polarization. We will specifically evaluate HIV's effects on liver macrophages using RNA-Seq, and will assess the contribution of EGFR signaling to HIV's effects on the macrophage population by performing inhibitor studies. We will also assess HIV's promotion of fibrogenesis using stellate cell cocultures. (3) Evaluate the effects of antiretroviral suppression of HIV on hepatic macrophages in vitro and in vivo. The latter studies will be carried out using hepatic fine needle aspirates frm HIV/HCV coinfected persons undergoing initiation of ART. We will test the hypothesis that successful HIV suppression partially but does not fully reverse the effect of HIV on alteration of the profibrogenic macrophage phenotype. These studies will shed great light on the contribution of the macrophage to HIV-associated liver fibrosis progression.