Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
PLoS One. 2012;7(6):e39565. doi: 10.1371/journal.pone.0039565. Epub 2012 Jun 25.
HIV-1 circulates both as free virus and within immune cells, with the level of free virus being predictive of clinical course. Both forms of HIV-1 cross the blood-brain barrier (BBB) and much progress has been made in understanding the mechanisms by which infected immune cells cross the blood-brain barrier BBB. How HIV-1 as free virus crosses the BBB is less clear as brain endothelial cells are CD4 and galactosylceramide negative. Here, we found that HIV-1 can use the mannose-6 phosphate receptor (M6PR) to cross the BBB. Brain perfusion studies showed that HIV-1 crossed the BBB of all brain regions consistent with the uniform distribution of M6PR. Ultrastructural studies showed HIV-1 crossed by a transcytotic pathway consistent with transport by M6PR. An in vitro model of the BBB was used to show that transport of HIV-1 was inhibited by mannose, mannan, and mannose-6 phosphate and that enzymatic removal of high mannose oligosaccharide residues from HIV-1 reduced transport. Wheatgerm agglutinin and protamine sulfate, substances known to greatly increase transcytosis of HIV-1 across the BBB in vivo, were shown to be active in the in vitro model and to act through a mannose-dependent mechanism. Transport was also cAMP and calcium-dependent, the latter suggesting that the cation-dependent member of the M6PR family mediates HIV-1 transport across the BBB. We conclude that M6PR is an important receptor used by HIV-1 to cross the BBB.
HIV-1 既以游离病毒的形式存在，也存在于免疫细胞内，游离病毒的水平可预测临床病程。这两种形式的 HIV-1 均可穿过血脑屏障（BBB），人们对感染免疫细胞如何穿过血脑屏障（BBB）的机制有了很多了解。游离 HIV-1 如何穿过 BBB 则不太清楚，因为脑内皮细胞缺乏 CD4 和半乳糖脑苷脂。在这里，我们发现 HIV-1 可以使用甘露糖-6-磷酸受体（M6PR）穿过 BBB。脑灌注研究表明，HIV-1 穿过所有脑区的 BBB，与 M6PR 的均匀分布一致。超微结构研究表明，HIV-1 通过胞吞作用途径穿过 BBB，与 M6PR 的转运一致。体外 BBB 模型用于表明甘露糖、甘露聚糖和甘露糖-6-磷酸可抑制 HIV-1 的转运，而 HIV-1 上高甘露糖寡糖残基的酶切去除会降低转运。麦胚凝集素和鱼精蛋白硫酸盐是体内大大增加 HIV-1 穿过 BBB 的胞吞作用的物质，在体外模型中显示出活性，并通过甘露糖依赖性机制起作用。转运还依赖于 cAMP 和钙，后者表明 M6PR 家族的阳离子依赖性成员介导 HIV-1 穿过 BBB 的转运。我们得出结论，M6PR 是 HIV-1 穿过 BBB 的重要受体。
