Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Department of Infectious Diseases, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
Sci Transl Med. 2014 May 14;6(236):236ra63. doi: 10.1126/scitranslmed.3008104.
Broadly neutralizing monoclonal antibodies (bnmAbs) that target the high-mannose patch centered around the glycan at position 332 on HIV Env are promising vaccine leads and therapeutic candidates because they effectively protect against mucosal SHIV challenge and strongly suppress SHIV viremia in established infection in macaque models. However, these antibodies demonstrate varying degrees of dependency on the N332 glycan site, and the origins of their neutralization breadth are not always obvious. By measuring neutralization on an extended range of glycan site viral variants, we found that some bnmAbs can use alternate N-linked glycans in the absence of the N332 glycan site and therefore neutralize a substantial number of viruses lacking the site. Furthermore, many of the antibodies can neutralize viruses in which the N332 glycan site is shifted to the 334 position. Finally, we found that a combination of three antibody families that target the high-mannose patch can lead to 99% neutralization coverage of a large panel of viruses containing the N332/N334 glycan site and up to 66% coverage for viruses that lack the N332/N334 glycan site. The results indicate that a diverse response against the high-mannose patch may provide near-equivalent coverage as a combination of bnmAbs targeting multiple epitopes. Additionally, the ability of some bnmAbs to use other N-linked glycan sites can help counter neutralization escape mediated by shifting of glycosylation sites. Overall, this work highlights the importance of promiscuous glycan binding properties in bnmAbs to the high-mannose patch for optimal antiviral activity in either protective or therapeutic modalities.
广泛中和单克隆抗体（bnmAbs）针对 HIV Env 上位于糖基化位置 332 周围的高甘露糖斑块，是有前途的疫苗先导和治疗候选物，因为它们能有效预防黏膜 SHIV 挑战，并在恒河猴模型中建立感染时强烈抑制 SHIV 病毒血症。然而，这些抗体对 N332 糖基化位点表现出不同程度的依赖性，其中和广度的起源并不总是显而易见。通过对广泛的糖基化位点病毒变体进行中和测量，我们发现一些 bnmAbs 可以在没有 N332 糖基化位点的情况下使用替代的 N 连接聚糖，因此可以中和大量缺乏该位点的病毒。此外，许多抗体可以中和 N332 糖基化位点转移到 334 位置的病毒。最后，我们发现靶向高甘露糖斑块的三种抗体家族的组合，可以导致针对包含 N332/N334 糖基化位点的大型病毒面板的 99%中和覆盖率，以及对缺乏 N332/N334 糖基化位点的病毒的 66%覆盖率。结果表明，针对高甘露糖斑块的多样化反应可能提供与针对多个表位的 bnmAbs 组合相当的覆盖范围。此外，一些 bnmAbs 使用其他 N 连接聚糖的能力可以帮助对抗由糖基化位点转移介导的中和逃逸。总的来说，这项工作强调了在保护性或治疗性模式中，针对高甘露糖斑块的 bnmAbs 具有混杂的聚糖结合特性对于最佳抗病毒活性的重要性。
