Lynch Rebecca M, Wong Patrick, Tran Lillian, O'Dell Sijy, Nason Martha C, Li Yuxing, Wu Xueling, Mascola John R
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
J Virol. 2015 Apr;89(8):4201-13. doi: 10.1128/JVI.03608-14. Epub 2015 Jan 28.
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 β23-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.
Some 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.
已从选定的HIV-1感染个体中分离出广泛中和抗体（bNAbs），并显示其可与包膜糖蛋白（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bNAbs具有抗性，这表明在慢性感染期间，HIV-1甚至可以逃脱广泛交叉反应抗体的作用。在此，我们评估这种病毒逃逸是否与病毒复制受损有关。VRC01类抗体靶向功能保守的CD4结合位点，并共享一种gp120识别的结构模式，其中包括对CD4受体的模拟。我们检查了天然存在的对VRC01敏感和耐药的病毒株，以及它们的突变敏感或耐药变体，并测试了VRC01敏感分离株YU2主干中的点突变。在几种情况下，VRC01抗性与CD4介导的病毒进入效率降低和病毒复制减少有关。Env的环D或β23-V5区域中的几个突变单独或组合可赋予对VRC01类抗体的高水平抗性，提示存在一种优先的逃逸途径。我们进一步使用来自分离出抗体VRC01的供体45的Env在体内绘制了VRC01诱导的逃逸途径。最初的逃逸突变，包括添加一个关键聚糖，发生在环D中，并与病毒复制受损有关；然而，补偿性突变恢复了完全的复制适应性。这些数据表明，从VRC01类抗体逃逸可降低病毒复制适应性，但补偿性变化可能解释了中和抗体在自然HIV-1感染过程中的有限影响。
自然HIV-1感染过程中产生的一些抗体可与病毒包膜糖蛋白上的保守区域结合，并有效中和大多数不同的HIV-1毒株。VRC01类抗体阻断病毒进入所必需的保守CD4受体结合位点相互作用，增加了病毒从抗体中和中逃逸可能对病毒功能产生有害影响的可能性。在此，我们表明从VRC01类抗体逃逸可能与病毒进入和复制受损有关；然而，在自然感染过程中，补偿性突变恢复了病毒正常复制的能力。
