Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: implications for the pathogenesis of HIV/hepatitis C virus-induced liver fibrosis.
Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: implications for the pathogenesis of HIV/hepatitis C virus-induced liver fibrosis.
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DOI：
10.1002/hep.23679
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发表时间：
2010-08
期刊：
影响因子：
13.5
通讯作者：
Bansal, Meena B.
中科院分区：
文献类型：
--
作者：
Tuyama, Ana C.;Hong, Feng;Saiman, Yedidya;Wang, Chuansheng;Ozkok, Derya;Mosoian, Arevik;Chen, Ping;Chen, Benjamin K.;Klotman, Mary E.;Bansal, Meena B.
与仅感染丙型肝炎病毒的患者相比，同时感染人类免疫缺陷病毒(HIV)和丙型肝炎病毒(丙型肝炎病毒)的患者发展得更快。在艾滋病毒/丙型肝炎合并感染的患者中，纤维化进展与艾滋病毒RNA水平相关，这表明艾滋病毒在肝纤维化形成中起直接作用。趋化因子(C-C基序)受体5(CCR5)和半胱氨酸-X-半胱氨酸受体4(CXCR4)是HIV进入细胞所需的两个主要辅助受体，表达于激活的肝星状细胞(HSCs)上，HSCs是肝脏中主要的纤维化细胞类型。因此，我们检查了HIV是否可以感染HSCs，探索了病毒进入的潜在机制，并评估了感染的影响，反映在HSCs将病毒转移到T淋巴细胞并引发促炎和促纤维化反应的能力。我们报道了实验室适应病毒HIV-IIIB(CXCR4嗜性或X4)和HIV-Bal(CCR5嗜性或R5)和HIV原代分离株可以感染人类星状细胞系LX-2和原代人类HSCs。在逆转录酶抑制剂叠氮胸苷存在或不存在的情况下，利用HIV-绿色荧光蛋白(GFP)表达的病毒构建物证实HIV进入HSC并在HSCs中表达基因。通过荧光激活细胞分选和免疫荧光染色，证实了原代HSCs亚群上的CD4表达。在抗CD4、抗CXCR4和抗CCR5存在下的阻断实验表明，HIV进入HSCs主要是CD4/趋化因子共受体不依赖的。HIV感染促进HSC I型胶原表达和促炎细胞因子单核细胞趋化蛋白-1的分泌。此外，在共培养系统中，感染的LX-2细胞能够将表达GFP的病毒转移到T淋巴细胞。综上所述，我们的结果提示HIV通过对HSC的影响在肝纤维化/炎症中发挥潜在作用。早期高效抗逆转录病毒治疗在HIV/丙型肝炎合并感染患者中的作用值得进一步研究。
Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) develop more rapid fibrosis than those infected with HCV only. In HIV/HCV-coinfected patients, fibrosis progression correlates with HIV RNA levels, suggesting a direct role of HIV in liver fibrogenesis. Chemokine (C-C motif) receptor 5 (CCR5) and cysteine-X-cysteine receptor 4 (CXCR4), the two major coreceptors required for HIV entry into cells, are expressed on activated hepatic stellate cells (HSCs), the principle fibrogenic cell type in the liver. We therefore examined whether HIV can infect HSCs, explored the potential mechanisms of viral entry, and assessed the impact of infection as reflected by the ability of HSCs to transfer virus to T lymphocytes and elicit a proinflammatory and profibrogenic response. We report that the laboratory-adapted viruses HIV-IIIB (CXCR4-tropic or X4) and HIV-BaL (CCR5-tropic or R5) and primary HIV isolates can infect both a human stellate cell line, LX-2, and primary human HSCs. HIV entry and gene expression in HSCs was confirmed using HIV–green fluorescent protein (GFP) expression viral constructs in the presence or absence of the reverse-transcriptase inhibitor azidothymidine. CD4 expression on a subset of primary HSCs was demonstrated using fluorescence-activated cell sorting and immunofluorescence staining. Blocking experiments in the presence of anti-CD4, anti-CXCR4, and anti-CCR5 revealed that HIV entry into HSCs is predominantly CD4/chemokine coreceptor-independent. HIV infection promoted HSC collagen I expression and secretion of the proinflammatory cytokine monocyte chemoattractant protein-1. Furthermore, infected LX-2 cells were capable of transferring GFP-expressing virus to T lymphocytes in a coculture system. Taken together, our results suggest a potential role of HIV in liver fibrosis/inflammation mediated through effects on HSCs. The role of early highly active antiretroviral therapy initiation in patients with HIV/HCV coinfection warrants further investigation.
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