Platelet Factor 4 Inhibits and Enhances HIV-1 Infection in a Concentration-Dependent Manner by Modulating Viral Attachment.
Platelet Factor 4 Inhibits and Enhances HIV-1 Infection in a Concentration-Dependent Manner by Modulating Viral Attachment.
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DOI：
10.1089/aid.2015.0344
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发表时间：
2016-06
影响因子：
1.5
通讯作者：
Z. Parker;A. Rux;Amber M. Riblett;Fang-Hua Lee;L. Rauova;D. Cines;M. Poncz;B. Sachais;R. Doms
中科院分区：
文献类型：
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作者：
Z. Parker;A. Rux;Amber M. Riblett;Fang-Hua Lee;L. Rauova;D. Cines;M. Poncz;B. Sachais;R. Doms
最近显示，血小板因子 4 (PF4) 可在体外抑制多种人类免疫缺陷病毒 1 型 (HIV-1) 分离株的感染。我们发现 PF4 的抑制作用仅限于规定的浓度范围，其中 PF4 主要以单体状态存在。在这些条件下，PF4 结合 HIV-1 包膜蛋白并抑制 HIV-1 附着到细胞表面。然而，当 PF4 浓度增加到主要以四聚体或更高级形式存在时，体外病毒感染就会增强。 PF4 中的突变将寡聚体平衡转向单体状态，或者通过使用四聚体 PF4 强烈结合的可溶性糖胺聚糖 (GAG) 来抑制增强。我们得出的结论是，在生理相关浓度下，寡聚 PF4 通过与病毒包膜蛋白以及细胞表面 GAG 相互作用，增强病毒对细胞表面的附着，从而增强 HIV-1 的感染。这种效应并非 HIV-1 所特有的，因为在某些但并非所有其他测试病毒中都观察到了增强作用。 PF4对HIV-1感染的双相作用表明，天然PF4不会成为有用的抗病毒剂，并且PF4可能通过增强骨髓中的病毒感染而导致HIV感染者中常见的血液学异常。
Platelet factor 4 (PF4) has been recently shown to inhibit infection by a broad range of human immunodeficiency virus type 1 (HIV-1) isolates in vitro. We found that the inhibitory effects of PF4 are limited to a defined concentration range where PF4 exists largely in a monomeric state. Under these conditions, PF4 bound the HIV-1 envelope protein and inhibited HIV-1 attachment to the cell surface. However, as concentrations increased to the point where PF4 exists largely in tetrameric or higher-order forms, viral infection in vitro was enhanced. Enhancement could be inhibited by mutations in PF4 that shift the oligomeric equilibrium toward the monomeric state, or by using soluble glycosaminoglycans (GAGs) to which tetrameric PF4 avidly binds. We conclude that at physiologically relevant concentrations, oligomeric PF4 enhances infection by HIV-1 by interacting with the viral envelope protein as well as cell surface GAGs, enhancing virus attachment to the cell surface. This effect was not specific to HIV-1, as enhancement was seen with some but not all other viruses tested. The biphasic effects of PF4 on HIV-1 infection suggest that native PF4 will not be a useful antiviral agent and that PF4 could contribute to the hematologic abnormalities commonly seen in HIV-infected individuals by enhancing virus infection in the bone marrow.