Raft localization of CXCR4 is primarily required for X4-tropic human immunodeficiency virus type 1 infection
Raft localization of CXCR4 is primarily required for X4-tropic human immunodeficiency virus type 1 infection
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DOI：
10.1016/j.virol.2008.12.033
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发表时间：
2009-03-30
期刊：
影响因子：
3.7
通讯作者：
Kubo, Yoshinao
中科院分区：
文献类型：
--
作者：
Kamiyama, Haruka;Yoshii, Hiroaki;Kubo, Yoshinao
人类免疫缺陷病毒 1 型 (HIV-1) 感染是由病毒包膜糖蛋白 gp120 与两种细胞表面蛋白 CD4 和趋化因子受体的连续相互作用引发的。允许 HIV-1 进入的两种最常见的趋化因子受体是 CCR5 和 CXCR4。 CD4 和 CCR5 主要定位于特定的质膜微区，称为筏，富含糖脂和胆固醇。然而，CXCR4 仅部分定位于筏区域。尽管raft结构域被认为参与HIV-1感染，但其在CXCR4-tropic（X4-tropic）病毒进入中的作用仍不清楚。在这里，我们使用了CD4非依赖性感染系统和胆固醇消耗诱导剂甲基-β-环糊精（M beta CD）的组合来解决X4嗜性病毒感染中筏结构域的需求。用 M beta CD 处理 CD4 阴性、CXCR4 阳性人类细胞可抑制 X4 嗜性菌株的 CD4 独立感染。即使当 CXCR4 在靶细胞上过度表达时，也观察到这种胆固醇消耗的抑制作用。 M beta CD 也能抑制可溶性 CD4 诱导的感染。 M beta CD 对 CXCR4 的细胞表面表达水平没有影响。与这些感染相反，M CD 治疗并不能抑制表达野生型 CD4 的细胞中依赖 CD4 的 HIV-1 感染。这项研究和之前的报告表明，位于非筏结构域的 CD4 突变体充当 HIV-1 受体，这表明 CXCR4 聚集在筏微结构域中，而不是 CD4，是 HIV-1 进入的关键步骤。 (c) 2008 Elsevier Inc. 保留所有权利。
Human immunodeficiency virus type 1 (HIV-1) infection is initiated by successive interactions of viral envelope glycoprotein gp120 with two cellular surface proteins, CD4 and chemokine receptor. The two most common chemokine receptors that allow HIV-1 entry are the CCR5 and CXCR4. The CD4 and CCR5 are mainly localized to the particular plasma membrane microdomains, termed raft, which is rich in glycolipids and cholesterol. However, the CXCR4 is localized only partially to the raft region. Although the raft domain is suggested to participate in HIV-1 infection, its role in entry of CXCR4-tropic (X4-tropic) virus is still unclear. Here, we used a combination of CD4-independent infection system and cholesterol-depletion-inducing reagent, methyl-beta-cyclodextrin (M beta CD), to address the requirement of raft domain in the X4-tropic virus infection. Treatment of CD4-negative, CXCR4-positive human cells with M beta CD inhibited CD4-independent infection of the X4-tropic strains. This inhibitory effect of the cholesterol depletion was observed even when the CXCR4 was over-expressed on the target cells. Soluble CD4-induced infection was also inhibited by M beta CD. The M beta CD had no effect on the levels of cell surface expression of CXCR4. In contrast to these infections, M CD treatment did not inhibit CD4-dependent HIV-1 infection in the wild type CD4-expressing cells. This study and previous reports showing that CD4 mutants localized to non-raft domains function as HIV-1 receptor indicate that CXCR4 clustering in the raft microdomains, rather than CD4, is the key step for the HIV-1 entry. (c) 2008 Elsevier Inc. All rights reserved.