Neutralization Resistance of Virological Synapse-Mediated HIV-1 Infection Is Regulated by the gp41 Cytoplasmic Tail
Neutralization Resistance of Virological Synapse-Mediated HIV-1 Infection Is Regulated by the gp41 Cytoplasmic Tail
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DOI：
10.1128/jvi.00230-12
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发表时间：
2012-07-01
影响因子：
5.4
通讯作者：
Chen, Benjamin K.
中科院分区：
文献类型：
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作者：
Durham, Natasha D.;Yewdall, Alice W.;Chen, Benjamin K.
人类免疫缺陷病毒1型（HIV-1）感染可以通过称为病毒学突触（VSs）的粘附接触从感染的T细胞有效地传播到未感染的T细胞。在这个过程中，细胞表面包膜糖蛋白（Env）启动粘附和病毒转移到未感染的受体细胞。先前的研究发现，一些hiv -1中和的患者血清在阻断vs介导的感染方面不如无细胞病毒感染有效。在这里，我们采用基于流式细胞术的敏感感染检测来测量hiv -1中和单克隆抗体（MAb）和hiv -1中和患者血清对无细胞感染和vs介导感染的抑制效力。在不同程度上，anti-Env mab对vs介导感染的抑制浓度（IC(50)s）明显高于无细胞感染。值得注意的是，MAb 17b结合了gp120上的cd4诱导（CD4i）表位，与无细胞接种相比，对vs介导的接种效果降低了72倍。gp41细胞质尾部（CT）的一个截短突变体在病毒颗粒成熟时不能调节Env的融合原性，但仍然可以参与细胞间感染，测试了其抵抗中和抗体的能力。Delta CT突变增加了中和抗体对细胞表面的染色，显著增强了vs介导感染的中和作用，并减少或没有对无细胞感染的影响，这取决于抗体。我们的研究结果表明，gp41 CT在细胞间感染过程中调节关键中和表位的暴露，并在免疫逃避中发挥重要作用。疫苗策略应考虑暴露在受感染细胞表面反映Env构象的免疫原，以增强对vs介导的HIV-1传播的保护。
Human immunodeficiency virus type 1 (HIV-1) infection can spread efficiently from infected to uninfected T cells through adhesive contacts called virological synapses (VSs). In this process, cell-surface envelope glycoprotein (Env) initiates adhesion and viral transfer into an uninfected recipient cell. Previous studies have found some HIV-1-neutralizing patient sera to be less effective at blocking VS-mediated infection than infection with cell-free virus. Here we employ sensitive flow cytometry-based infection assays to measure the inhibitory potency of HIV-1-neutralizing monoclonal antibodies (MAb) and HIV-1-neutralizing patient sera against cell-free and VS-mediated infection. To various degrees, anti-Env MAbs exhibited significantly higher 50% inhibitory concentration (IC(50)s) against VS-mediated infection than cell-free infection. Notably, the MAb 17b, which binds a CD4-induced (CD4i) epitope on gp120, displayed a 72-fold reduced efficacy against VS-mediated inocula compared to cell-free inocula. A mutant with truncation mutation in the gp41 cytoplasmic tail (CT) which is unable to modulate Env fusogenicity in response to virus particle maturation but which can still engage in cell-to-cell infection was tested for the ability to resist neutralizing antibodies. The Delta CT mutation increased cell surface staining by neutralizing antibodies, significantly enhanced neutralization of VS-mediated infection, and had reduced or no effect on cell-free infection, depending upon the antibody. Our results suggest that the gp41 CT regulates the exposure of key neutralizing epitopes during cell-to-cell infection and plays an important role in immune evasion. Vaccine strategies should consider immunogens that reflect Env conformations exposed on the infected cell surface to enhance protection against VS-mediated HIV-1 spread.