Loss of the N-linked glycosylation site at position 386 in the HIV envelope V4 region enhances macrophage tropism and is associated with dementia
Loss of the N-linked glycosylation site at position 386 in the HIV envelope V4 region enhances macrophage tropism and is associated with dementia
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DOI：
10.1016/j.virol.2007.05.029
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发表时间：
2007-10-10
期刊：
影响因子：
3.7
通讯作者：
Gabuzda, Dana
中科院分区：
文献类型：
--
作者：
Dunfee, Rebecca L.;Thomas, Elaine R.;Gabuzda, Dana
HIV感染中枢神经系统（CNS）中的巨噬细胞和小胶质细胞。增强HIV巨噬细胞/小胶质细胞向性的机制尚不清楚。在这里，我们在gp120的V4区域发现了一种HIV Env变异，Asp 386 (D386)，它消除了386位置的一个n-链糖基化位点，增强了巨噬细胞中的病毒复制，并且与非HAD患者相比，在艾滋病患者伴HIV相关痴呆（HAD）中出现的频率更高。D386增强了HIV在巨噬细胞中的进入和复制，但在小胶质细胞或外周血单核细胞中没有，可能是由于这些细胞类型的糖基化不同。UK1br Env中的D386N突变恢复了n -连接的聚糖位点，降低了对IgG1b12 （b12）单克隆抗体的中和敏感性，该单克隆抗体识别与CD4结合位点重叠的保守中和表位。分子模型表明，386位聚糖的缺失增加了gp120上CD4和b12结合位点的暴露。与非HAD患者（7%,n=99; p）相比，HAD患者（26%,n=185）的Envs在386时丢失一个聚糖的频率更高
HIV infects macrophages and microglia in the central nervous system (CNS). Mechanisms that enhance HIV macrophage/microglial tropism are not well understood. Here, we identify an HIV Env variant in the V4 region of gp120, Asp 386 (D386), that eliminates an N-linked glycosylation site at position 386, enhances viral replication in macrophages, and is present at a higher frequency in AIDS patients with HIV-associated dementia (HAD) compared with non-HAD patients. D386 enhances HIV entry and replication in macrophages but not in microglia or peripheral blood mononuclear cells, possibly due to differential glycosylation in these cell types. A D386N mutation in the UK1br Env, which restores the N-linked glycan site, reduced neutralization sensitivity to the IgG1b12 (b12) monoclonal antibody, which recognizes a conserved neutralization epitope that overlaps the CD4 binding site. Molecular modeling suggested that loss of the glycan at position 386 increases exposure of the CD4 and b 12 binding sites on gp 120. Loss of a glycan at 386 was more frequent in Envs from HAD patients (26%; n=185) compared with non-HAD patients (7%; n=99; p