SERINC5-Mediated Restriction of HIV-1 Infectivity Correlates with Resistance to Cholesterol Extraction but Not with Lipid Order of Viral Membrane.
SERINC5-Mediated Restriction of HIV-1 Infectivity Correlates with Resistance to Cholesterol Extraction but Not with Lipid Order of Viral Membrane.
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DOI：
10.3390/v14081636
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发表时间：
2022-07-27
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丝氨酸蛋白酶5（SER 5）是一种蛋白质，其在掺入病毒体后通过干扰Env糖蛋白促进病毒融合的能力来抑制HIV-1感染性。SER 5拮抗HIV-1融合的机制还不清楚。最近一项对SER 5结构的研究揭示了一个脂质结合口袋，这表明它具有隔离脂质的能力。这一发现，沿着有充分证据表明病毒脂质，特别是胆固醇对HIV-1感染性的调节，促使我们研究SER 5对HIV-1膜一般脂质顺序的影响。使用两种不同的脂质顺序探针分析了携带SER 5敏感性HXB 2-Env并含有SER 5或SER 2（一种缺乏抗病毒活性的对照蛋白）的假病毒。我们表明，HER 5的掺入不会明显影响假病毒的脂质顺序。尽管病毒胆固醇提取物降低了HIV-1感染性，但SER 5+病毒对胆固醇提取物的敏感性低于对照样品。相反，病毒对胆固醇氧化的敏感性不受SER 5掺入的影响。鞘磷脂螯合胆固醇的水解释放对胆固醇提取的表观抗性影响极小。基于这些结果，我们提出，负责SER 5+病毒的残余感染性的更稳定的Env糖蛋白的亚群对病毒膜的胆固醇含量不太敏感。
Serine incorporator 5 (SER5) is a protein that upon incorporation into virions inhibits HIV-1 infectivity by interfering with the ability of the Env glycoprotein to promote viral fusion. The mechanisms by which SER5 antagonizes HIV-1 fusion are not well understood. A recent study of SER5’s structure revealed a lipid-binding pocket, suggesting the ability to sequester lipids. This finding, along with the well-documented modulation of HIV-1 infectivity by viral lipids, especially cholesterol, prompted our examination of SER5′s effect on the general lipid order of the HIV-1 membrane. Pseudoviruses bearing the SER5-sensitive HXB2-Env and containing SER5 or SER2, a control protein that lacks antiviral activity, were analyzed using two distinct lipid-order probes. We show that SER5 incorporation does not noticeably affect the lipid order of pseudoviruses. Although viral cholesterol extraction reduces HIV-1 infectivity, SER5+ viruses are less sensitive to cholesterol extraction than the control samples. In contrast, the virus’ sensitivity to cholesterol oxidation was not affected by SER5 incorporation. The hydrolytic release of sphingomyelin-sequestered cholesterol had a minimal impact on the apparent resistance to cholesterol extraction. Based on these results, we propose that a subpopulation of more stable Env glycoproteins responsible for the residual infectivity of SER5+ viruses is less sensitive to the cholesterol content of the viral membrane.
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