X4 Human immunodeficiency virus type 1 gp120 promotes human hepatic stellate cell activation and collagen I expression through interactions with CXCR4.
X4 Human immunodeficiency virus type 1 gp120 promotes human hepatic stellate cell activation and collagen I expression through interactions with CXCR4.
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X4 人类免疫缺陷病毒 1 型 gp120 通过与 CXCR4 相互作用促进人肝星状细胞活化和 I 型胶原蛋白表达
DOI：
10.1371/journal.pone.0033659
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bansal MB
中科院分区：
文献类型：
--
作者：
Hong F;Saiman Y;Si C;Mosoian A;Bansal MB
背景与目的HIV-1和HCV合并感染的患者比HCV合并感染的患者发生肝纤维化的速度更快。HIV RNA水平与纤维化进展相关，暗示HIV直接参与纤维化过程。虽然活化的肝星状细胞（hsc）表达两种主要的HIV趋化因子共受体CXCR4和CCR5，但关于HIV-1包膜蛋白gp120对hsc的促纤维化作用知之甚少。因此，我们检测了X4 gp120在体外对HSC活化、I型胶原表达和潜在信号通路的影响，并检测了gp120在HIV/HCV共感染肝脏中的体内表达。方法用X4 gp120刺激原代人HSC和LX-2细胞，采用qRT-PCR和Western blot检测cxcr4靶向shRNA或抗cxcr4中和抗体的表达情况。下游细胞内信号通路通过Western blot和特异性通路抑制剂预处理进行评估。对HIV/HCV合并感染的肝活检进行Gp120免疫染色。结果X4 gp 120可显著提高α -平滑肌肌动蛋白（a-SMA）和I型胶原的表达，并可通过cxcr4靶向shRNA或抗cxcr4中和抗体阻断造血干细胞的表达。此外，X4 gp120促进细胞外信号调节激酶（ERK） 1/2磷酸化，ERK抑制剂预处理可减弱HSC活化和I型胶原的表达。gp120在HIV/HCV合并感染的肝脏中呈正弦染色。结论X4 HIV-1 gp120通过与CXCR4的相互作用在活化的hsc上促进纤维化。CXCR4小分子抑制剂的可用性使其成为HIV/HCV合并感染患者的潜在抗纤维化靶点。
Background & Aims Patients coinfected with HIV-1 and HCV develop more rapid liver fibrosis than patients monoinfected with HCV. HIV RNA levels correlate with fibrosis progression implicating HIV directly in the fibrotic process. While activated hepatic stellate cells (HSCs) express the 2 major HIV chemokine coreceptors, CXCR4 and CCR5, little is known about the pro-fibrogenic effects of the HIV-1 envelope protein, gp120, on HSCs. We therefore examined the in vitro impact of X4 gp120 on HSC activation, collagen I expression, and underlying signaling pathways and examined the in vivo expression of gp120 in HIV/HCV coinfected livers. Methods Primary human HSCs and LX-2 cells, a human HSC line, were challenged with X4 gp120 and expression of fibrogenic markers assessed by qRT-PCR and Western blot +/− either CXCR4-targeted shRNA or anti-CXCR4 neutralizing antibody. Downstream intracellular signaling pathways were evaluated with Western blot and pre-treatment with specific pathway inhibitors. Gp120 immunostaining was performed on HIV/HCV coinfected liver biopsies. Results X4 gp 120 significantly increased expression of alpha-smooth muscle actin (a-SMA) and collagen I in HSCs which was blocked by pre-incubation with either CXCR4-targeted shRNA or anti-CXCR4 neutralizing antibody. Furthermore, X4 gp120 promoted Extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and pretreatment with an ERK inhibitor attenuated HSC activation and collagen I expression. Sinusoidal staining for gp120 was evident in HIV/HCV coinfected livers. Conclusions X4 HIV-1 gp120 is pro-fibrogenic through its interactions with CXCR4 on activated HSCs. The availability of small molecule inhibitors to CXCR4 make this a potential anti-fibrotic target in HIV/HCV coinfected patients.
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影响因子：
56.9
作者：
Feng, Y;Broder, CC;Berger, EA
通讯作者：
Berger, EA
影响因子：
12.7
作者：
Blackard, JT;Komurian-Pradel, F;Chung, RT
通讯作者：
Chung, RT
影响因子：
4.8
作者：
Balasubramanian, A;Ganju, RK;Groopman, JE
通讯作者：
Groopman, JE
影响因子：
2.5
作者：
de Ledinghen, V.;Barreiro, P.;Soriano, V.
通讯作者：
Soriano, V.
影响因子：
6.4
作者：
Munshi, N;Balasubramanian, A;Groopman, JE
通讯作者：
Groopman, JE