期刊
GLYCOBIOLOGY
卷 20, 期 7, 页码 812-823出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/glycob/cwq020
关键词
2G12; glycan array; GnT I-deficient HEK 293S; human immunodeficiency virus; kifunensine; oligomannose; vaccine; yeast
资金
- UK Research Councils' Basic Technology initiative 'Glycoarrays' [GR/S79268]
- UK Engineering and Physical Research Councils Translational [EP/G037604/1]
- NCI Alliance of Glycobiologists for Detection of Cancer and Cancer Risk [U01 CA128416]
- Fundacao para a Ciencia e Tecnologia, Portugal [SFRH/BPD/26515/2006]
- EPSRC [EP/G037604/1] Funding Source: UKRI
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/26515/2006] Funding Source: FCT
- Engineering and Physical Sciences Research Council [EP/G037604/1, GR/S79268/02] Funding Source: researchfish
Immunologically, self carbohydrates protect the HIV-1 surface glycoprotein, gp120, from antibody recognition. However, one broadly neutralizing antibody, 2G12, neutralizes primary viral isolates by direct recognition of Man alpha 1 -> 2Man motifs formed by the host-derived oligomannose glycans of the viral envelope. Immunogens, capable of eliciting antibodies of similar specificity to 2G12, are therefore candidates for HIV/AIDS vaccine development. In this context, it is known that the yeast mannan polysaccharides exhibit significant antigenic mimicry with the glycans of HIV-1. Here, we report that modulation of yeast polysaccharide biosynthesis directly controls the molecular specificity of cross-reactive antibodies to self oligomannose glycans. Saccharomyces cerevisiae mannans are typically terminated by alpha 1 -> 3-linked mannoses that cap a Man alpha 1 -> 2Man motif that otherwise closely resembles the part of the oligomannose epitope recognized by 2G12. Immunization with S. cerevisiae deficient for the alpha 1 -> 3 mannosyltransferase gene (delta Mnn1), but not with wild-type S. cerevisiae, reproducibly elicited antibodies to the self oligomannose glycans. Carbohydrate microarray analysis of delta Mnn1 immune sera revealed fine carbohydrate specificity to Man alpha 1 -> 2Man units, closely matching that of 2G12. These specificities were further corroborated by enzyme-linked immunosorbent assay with chemically defined glycoforms of gp120. These antibodies exhibited remarkable similarity in the carbohydrate specificity to 2G12 and displayed statistically significant, albeit extremely weak, neutralization of HIV-1 compared to control immune sera. These data confirm the Man alpha 1 -> 2Man motif as the primary carbohydrate neutralization determinant of HIV-1 and show that the genetic modulation of microbial polysaccharides is a route towards immunogens capable of eliciting antibody responses to the glycans of HIV-1.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据