Doores Katie J, Kong Leopold, Krumm Stefanie A, Le Khoa M, Sok Devin, Laserson Uri, Garces Fernando, Poignard Pascal, Wilson Ian A, Burton Dennis R
Department of Infectious Diseases, King's College London, Faculty of Life Sciences and Medicine, Guy's Hospital, London, United Kingdom
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, USA Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
J Virol. 2015 Jan 15;89(2):1105-18. doi: 10.1128/JVI.02905-14. Epub 2014 Nov 5.
The high-mannose patch of human immunodeficiency virus (HIV) envelope (Env) elicits broadly neutralizing antibodies (bnAbs) during natural infection relatively frequently, and consequently, this region has become a major target of vaccine design. However, it has also become clear that antibody recognition of the region is complex due, at least in part, to variability in neighboring loops and glycans critical to the epitopes. bnAbs against this region have some shared features and some distinguishing features that are crucial to understand in order to design optimal immunogens that can induce different classes of bnAbs against this region. Here, we compare two branches of a single antibody lineage, in which all members recognize the high-mannose patch. One branch (prototype bnAb PGT128) has a 6-amino-acid insertion in CDRH2 that is crucial for broad neutralization. Antibodies in this branch appear to favor a glycan site at N332 on gp120, and somatic hypermutation is required to accommodate the neighboring V1 loop glycans and glycan heterogeneity. The other branch (prototype bnAb PGT130) lacks the CDRH2 insertion. Antibodies in this branch are noticeably effective at neutralizing viruses with an alternate N334 glycan site but are less able to accommodate glycan heterogeneity. We identify a new somatic variant within this branch that is predominantly dependent on N334. The crystal structure of PGT130 offers insight into differences from PGT128. We conclude that different immunogens may be required to elicit bnAbs that have the optimal characteristics of the two branches of the lineage described.
Development of an HIV vaccine is of vital importance for prevention of new infections, and it is thought that elicitation of HIV bnAbs will be an important component of an effective vaccine. Increasingly, bnAbs that bind to the cluster of high-mannose glycans on the HIV envelope glycoprotein, gp120, are being highlighted as important templates for vaccine design. In particular, bnAbs from IAVI donor 36 (PGT125 to PGT131) have been shown to be extremely broad and potent. Combination of these bnAbs enhanced neutralization breadth considerably, suggesting that an optimal immunogen should elicit several antibodies from this family. Here we study the evolution of this antibody family to inform immunogen design. We identify two classes of bnAbs that differ in their recognition of the high-mannose patch and show that different immunogens may be required to elicit these different classes.
人类免疫缺陷病毒（HIV）包膜（Env）的高甘露糖区域在自然感染期间相对频繁地引发广泛中和抗体（bnAbs），因此，该区域已成为疫苗设计的主要靶点。然而，也很明显，该区域的抗体识别很复杂，至少部分原因是相邻环和对表位至关重要的聚糖的变异性。针对该区域的bnAbs具有一些共同特征和一些独特特征，为了设计能够诱导针对该区域的不同类别bnAbs的最佳免疫原，了解这些特征至关重要。在这里，我们比较了单一抗体谱系的两个分支，其中所有成员都识别高甘露糖区域。一个分支（原型bnAb PGT128）在CDRH2中有一个6个氨基酸的插入，这对广泛中和至关重要。该分支中的抗体似乎倾向于gp120上N332处的聚糖位点，并且需要体细胞超突变来适应相邻的V1环聚糖和聚糖异质性。另一个分支（原型bnAb PGT130）缺乏CDRH2插入。该分支中的抗体在中和具有替代N334聚糖位点的病毒方面非常有效，但不太能够适应聚糖异质性。我们在该分支中鉴定出一种主要依赖N334的新体细胞变体。PGT130的晶体结构揭示了与PGT128的差异。我们得出结论，可能需要不同的免疫原来引发具有所述谱系两个分支最佳特征的bnAbs。
开发HIV疫苗对于预防新感染至关重要，并且人们认为引发HIV bnAbs将是有效疫苗的重要组成部分。越来越多地，与HIV包膜糖蛋白gp120上的高甘露糖聚糖簇结合的bnAbs被突出作为疫苗设计的重要模板。特别是，来自IAVI供体36（PGT125至PGT131）的bnAbs已被证明具有极其广泛和强大的中和能力。这些bnAbs的组合显著增强了中和广度，表明最佳免疫原应引发该家族的几种抗体。在这里，我们研究该抗体家族的进化以指导免疫原设计。我们鉴定出两类在识别高甘露糖区域方面存在差异的bnAbs，并表明可能需要不同的免疫原来引发这些不同类别。
