Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor
Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor
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DOI：
10.1073/pnas.1207314109
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发表时间：
2012-06-12
影响因子：
11.1
通讯作者：
Lusso, Paolo
中科院分区：
文献类型：
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作者：
Auerbach, David J.;Lin, Yin;Lusso, Paolo
HIV-1感染的自然历史在不同的个体中是高度可变的，从快速进展的过程到长期无症状的感染。疾病进展速度的一个主要决定因素是体内HIV-1复制水平，这是由免疫细胞和炎症细胞表达的细胞因子和趋化因子的复杂网络调节的。趋化因子系统通过特定的趋化因子受体（最显著的是CCR5和CXCR4）作为HIV-1进入细胞表面的辅助受体，在控制HIV-1复制中起着至关重要的作用；因此，自然结合这些辅助受体的趋化因子作为HIV-1的内源性抑制剂。在这里，我们发现CXC趋化因子CXCL4 （PF-4）是血小板α颗粒中含量最丰富的蛋白质，是HIV-1感染的广谱抑制剂。与其他已知的hiv抑制趋化因子不同，CXCL4抑制大多数HIV-1原代分离株的感染，无论其辅助受体使用表型或遗传亚型如何。与缺乏病毒表型特异性相一致，HIV-1感染的阻断发生在病毒附着和进入的水平上，通过一种独特的机制，包括CXCL4与主要病毒包膜糖蛋白gp120的直接相互作用。CXCL4的结合位点被定位到gp120外结构域靠近cd4结合位点的区域。鉴定血小板来源的趋化因子作为内源性抗病毒因子可能与HIV-1感染的发病机制和治疗有关。
The natural history of HIV-1 infection is highly variable in different individuals, spanning from a rapidly progressive course to a long-term asymptomatic infection. A major determinant of the pace of disease progression is the in vivo level of HIV-1 replication, which is regulated by a complex network of cytokines and chemokines expressed by immune and inflammatory cells. The chemokine system is critically involved in the control of HIV-1 replication by virtue of the role played by specific chemokine receptors, most notably CCR5 and CXCR4, as cell-surface coreceptors for HIV-1 entry; hence, the chemokines that naturally bind such coreceptors act as endogenous inhibitors of HIV-1. Here, we show that the CXC chemokine CXCL4 (PF-4), the most abundant protein contained within the alpha-granules of platelets, is a broad-spectrum inhibitor of HIV-1 infection. Unlike other known HIV-suppressive chemokines, CXCL4 inhibits infection by the majority of primary HIV-1 isolates regardless of their coreceptor-usage phenotype or genetic subtype. Consistent with the lack of viral phenotype specificity, blockade of HIV-1 infection occurs at the level of virus attachment and entry via a unique mechanism that involves direct interaction of CXCL4 with the major viral envelope glycoprotein, gp120. The binding site for CXCL4 was mapped to a region of the gp120 outer domain proximal to the CD4-binding site. The identification of a platelet-derived chemokine as an endogenous antiviral factor may have relevance for the pathogenesis and treatment of HIV-1 infection.