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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor
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Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor

机译：鉴定血小板衍生的趋化因子CXCL4 / PF-4作为广谱HIV-1抑制剂

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摘要

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 α-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.
机译：HIV-1感染的自然史在不同个体中变化很大，从快速进展到长期无症状感染。疾病进展速度的主要决定因素是体内HIV-1复制的水平，该水平受免疫和炎性细胞表达的复杂的细胞因子和趋化因子网络的调节。趋化因子系统由于特定的趋化因子受体（最明显的是CCR5和CXCR4）作为进入HIV-1的细胞表面共受体而发挥的作用，因此其在控制HIV-1复制中至关重要。因此，天然结合此类共受体的趋化因子可作为HIV-1的内源性抑制剂。在这里，我们显示CXC趋化因子CXCL4（PF-4）是血小板α颗粒中含量最高的蛋白质，是HIV-1感染的广谱抑制剂。与其他已知的抑制HIV的趋化因子不同，CXCL4抑制大多数主要HIV-1分离株的感染，无论其共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感染的阻断是通过独特的机制在病毒附着和进入的水平发生的，该机制涉及CXCL4与主要病毒包膜糖蛋白gp120的直接相互作用。 CXCL4的结合位点被映射到gp120外域的CD4结合位点附近的区域。血小板源趋化因子作为内源性抗病毒因子的鉴定可能与HIV-1感染的发病机理和治疗有关。

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    David J.Auerbach; Yin Lin; Huiyi Miao; Raffaello Cimbro; Michelle J.DiFiore; Monica E.Gianoiini; Lucinda Furci; Priscilla Biswas; Anthony S.Fauci; Paolo Lusso;

  • 作者单位

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892,Global Bioassays and Technology, Teva Biopharmaceuticals, Rockville,MD 20850;

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892,Department of Regenerative Medicine, Stem Cells, and Gene Therapy,San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy;

    Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milan, Italy;

    Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milan, Italy;

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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