HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies
HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies
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DOI：
10.1128/jvi.03608-14
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发表时间：
2015-04-01
影响因子：
5.4
通讯作者：
Mascola, John R.
中科院分区：
文献类型：
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作者：
Lynch, Rebecca M.;Wong, Patrick;Mascola, John R.
广泛中和抗体（bNAb）已从选定的HIV-1感染者中分离出来，并显示与包膜糖蛋白（Env）上的保守位点结合。然而，这些供体中的循环血浆病毒通常对自体分离的bNAb具有抗性，这表明在慢性感染期间，HIV-1甚至可以逃避广泛的交叉反应性抗体。在这里，我们评估这种病毒逃逸是否与病毒复制受损有关。VRC 01类抗体靶向功能保守的CD 4结合位点，并共享gp 120识别的结构模式，包括模拟CD 4受体。我们研究了自然发生的VRC 01敏感和耐药病毒株，以及它们的突变敏感或耐药变异体，并测试了VRC 01敏感分离株YU 2骨架中的点突变。在一些情况下，VRC 01耐药性与CD 4介导的病毒进入效率降低和病毒复制减少有关。Env的D环或β 23-V5区中的几个突变（单独或组合）赋予了对VRC 01类抗体的高水平抗性，表明了优选的逃逸途径。我们使用来自供体45的Envs进一步绘制了VRC 01诱导的体内逃逸途径，从供体45中分离出抗体VRC 01。最初的逃逸突变，包括增加一个关键的聚糖，发生在环D，并与受损的病毒复制;然而，补偿突变恢复完整的复制健身。这些数据表明，逃避VRC 01类抗体可以减少病毒的复制健身，但补偿性的变化可以解释自然HIV-1 infection.IMPORTANCESome中和抗体的过程中产生的影响有限的自然HIV-1感染过程中出现的抗体结合到病毒包膜糖蛋白的保守区域，并有力地中和大多数不同的HIV-1株。VRC 01类抗体阻断了病毒进入所必需的保守的CD 4受体结合位点相互作用，提高了病毒逃避抗体中和可能对病毒功能产生有害影响的可能性。在这里，我们表明，从VRC 01类抗体逃逸可能与受损的病毒进入和复制有关;然而，在自然感染过程中，补偿突变恢复了病毒正常复制的能力。
Broadly neutralizing antibodies (bNAbs) have been isolated from selected HIV-1-infected individuals and shown to bind to conserved sites on the envelope glycoprotein (Env). However, circulating plasma virus in these donors is usually resistant to autologous isolated bNAbs, indicating that during chronic infection, HIV-1 can escape from even broadly cross-reactive antibodies. Here, we evaluate if such viral escape is associated with an impairment of viral replication. Antibodies of the VRC01 class target the functionally conserved CD4 binding site and share a structural mode of gp120 recognition that includes mimicry of the CD4 receptor. We examined naturally occurring VRC01-sensitive and -resistant viral strains, as well as their mutated sensitive or resistant variants, and tested point mutations in the backbone of the VRC01-sensitive isolate YU2. In several cases, VRC01 resistance was associated with a reduced efficiency of CD4-mediated viral entry and diminished viral replication. Several mutations, alone or in combination, in the loop D or beta 23-V5 region of Env conferred a high level of resistance to VRC01 class antibodies, suggesting a preferred escape pathway. We further mapped the VRC01-induced escape pathway in vivo using Envs from donor 45, from whom antibody VRC01 was isolated. Initial escape mutations, including the addition of a key glycan, occurred in loop D and were associated with impaired viral replication; however, compensatory mutations restored full replicative fitness. These data demonstrate that escape from VRC01 class antibodies can diminish viral replicative fitness, but compensatory changes may explain the limited impact of neutralizing antibodies during the course of natural HIV-1 infection.IMPORTANCESome antibodies that arise during natural HIV-1 infection bind to conserved regions on the virus envelope glycoprotein and potently neutralize the majority of diverse HIV-1 strains. The VRC01 class of antibodies blocks the conserved CD4 receptor binding site interaction that is necessary for viral entry, raising the possibility that viral escape from antibody neutralization might exert detrimental effects on viral function. Here, we show that escape from VRC01 class antibodies can be associated with impaired viral entry and replication; however, during the course of natural infection, compensatory mutations restore the ability of the virus to replicate normally.