Broad Neutralization of Human Immunodeficiency Virus Type 1 Mediated by Plasma Antibodies against the gp41 Membrane Proximal External Region

We identified three cross-neutralizing plasma samples with high-titer anti-membrane proximal external region (MPER) peptide binding antibodies from among 156 chronically human immunodeficiency virus type 1-infected individuals. In order to establish if these antibodies were directly responsible for the observed neutralization breadth, we used MPER-coated magnetic beads to deplete plasmas of these specific antibodies. Depletion of anti-MPER antibodies from BB34, CAP206, and SAC21 resulted in 77%, 68%, and 46% decreases, respectively, in the number of viruses neutralized. Antibodies eluted from the beads showed neutralization profiles similar to those of the original plasmas, with potencies comparable to those of the known anti-MPER monoclonal antibodies (MAbs), 4E10, 2F5, and Z13e1. The anti-MPER neutralizing antibodies in BB34 were present in the immunoglobulin G3 subclass-enriched fraction. Alanine scanning of the MPER showed that the antibodies from these three plasmas had specificities distinct from those of the known MAbs, requiring one to three crucial residues at positions 670, 673, and 674. These data demonstrate the existence of MPER-specific cross-neutralizing antibodies in plasma, although the ability to elicit such potent antiviral antibodies during natural infection appears to be rare. Nevertheless, the identification of three novel antibody specificities within the MPER supports its further study as a promising target for vaccine design.

我们从156名慢性1型人类免疫缺陷病毒感染个体中鉴定出3份具有高效价抗膜近外区（MPER）肽结合抗体的交叉中和血浆样本。为了确定这些抗体是否直接导致所观察到的中和广度，我们使用MPER包被的磁珠去除血浆中的这些特异性抗体。从BB34、CAP206和SAC21中去除抗MPER抗体后，被中和的病毒数量分别减少了77%、68%和46%。从磁珠上洗脱下来的抗体显示出与原始血浆相似的中和谱，其效力与已知的抗MPER单克隆抗体（MAb）4E10、2F5和Z13e1相当。BB34中的抗MPER中和抗体存在于富含免疫球蛋白G3亚类的组分中。对MPER进行丙氨酸扫描显示，来自这3份血浆的抗体具有与已知单克隆抗体不同的特异性，需要670、673和674位的1 - 3个关键残基。这些数据表明血浆中存在MPER特异性交叉中和抗体，尽管在自然感染过程中诱导出如此强效的抗病毒抗体的能力似乎很罕见。然而，在MPER中鉴定出3种新的抗体特异性支持将其作为疫苗设计的一个有希望的靶点进行进一步研究。