Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection
Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection
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DOI：
10.1074/jbc.m116.718684
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发表时间：
2016-07-01
影响因子：
4.8
通讯作者：
Makhatadze, George I.
中科院分区：
文献类型：
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作者：
LoRicco, Josephine G.;Xu, Changmingzi Sherry;Makhatadze, George I.
最近的体外研究表明，在健康和艾滋病毒感染男性的精液中发现的淀粉样纤维，以及精液本身，可以显著提高艾滋病毒感染率。精液纤维是由来自精液的多个自然产生的多肽片段组成的。最具特点的是SEVI(精液来源的病毒感染增强剂)，由前列腺酸性磷酸酶残基248-286组成，以及SEM1纤维，由精胶1残基86-107组成。精液纤维拮抗剂的小分子筛选发现了四种降低精液介导的HIV-1感染力增强的化合物。其中一种是没食子酸，此前有报道称，它可以拮抗其他淀粉样蛋白并发挥抗炎作用。为了更好地了解没食子酸改变精液淀粉样蛋白的性质的机制，我们进行了生物物理测量(原子力显微镜、电子显微镜、共聚焦显微镜、硫代黄素T和刚果红荧光分析、Zeta电位测量)和定量分析没食子酸在精液介导的HIV感染和炎症中的作用。我们的结果表明，没食子酸与SEVI和SEM1纤维结合，并对其表面静电进行修饰，使其阳离子减少。此外，没食子酸可降低精液对HIV感染的促进作用，但不能降低精液诱导的炎症反应。总之，这些观察确定没食子酸是一种非多阴离子化合物，可以抑制精液介导的艾滋病毒感染的增强，并表明将没食子酸加入到针对艾滋病毒和促进病毒感染的宿主成分的多组分杀菌剂中具有潜在的用途。
Recent in vitro studies have demonstrated that amyloid fibrils found in semen from healthy and HIV-infected men, as well as semen itself, can markedly enhance HIV infection rates. Semen fibrils are made up of multiple naturally occurring peptide fragments derived from semen. The best characterized of these fibrils are SEVI (semen-derived enhancer of viral infection), made up of residues 248-286 of prostatic acidic phosphatase, and the SEM1 fibrils, made up of residues 86-107 of semenogelin 1. A small molecule screen for antagonists of semen fibrils identified four compounds that lowered semen-mediated enhancement of HIV-1 infectivity. One of the four, gallic acid, was previously reported to antagonize other amyloids and to exert anti-inflammatory effects. To better understand the mechanism by which gallic acid modifies the properties of semen amyloids, we performed biophysical measurements (atomic force microscopy, electron microscopy, confocal microscopy, thioflavin T and Congo Red fluorescence assays, zeta potential measurements) and quantitative assays on the effects of gallic acid on semen-mediated enhancement of HIV infection and inflammation. Our results demonstrate that gallic acid binds to both SEVI and SEM1 fibrils and modifies their surface electrostatics to render them less cationic. In addition, gallic acid decreased semen-mediated enhancement of HIV infection but did not decrease the inflammatory response induced by semen. Together, these observations identify gallic acid as a non-polyanionic compound that inhibits semen-mediated enhancement of HIV infection and suggest the potential utility of incorporating gallic acid into a multicomponent microbicide targeting both the HIV virus and host components that promote viral infection.