title: Polysaccharide mimicry of the epitope of the broadly neutralizing anti-HIV antibody, 2G12, induces enhanced antibody responses to self oligomannose glycans.
abstract: 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 Manalpha1-->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 alpha1-->3-linked mannoses that cap a Manalpha1-->2Man motif that otherwise closely resembles the part of the oligomannose epitope recognized by 2G12. Immunization with S. cerevisiae deficient for the alpha1-->3 mannosyltransferase gene (DeltaMnn1), but not with wild-type S. cerevisiae, reproducibly elicited antibodies to the self oligomannose glycans. Carbohydrate microarray analysis of DeltaMnn1 immune sera revealed fine carbohydrate specificity to Manalpha1-->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 Manalpha1-->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.
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: D Cameron
authors.initials: DC
authors.lastname: Dunlop
authors.forename: Camille
authors.initials: C
authors.lastname: Bonomelli
authors.forename: Fatma
authors.initials: F
authors.lastname: Mansab
authors.forename: Snezana
authors.initials: S
authors.lastname: Vasiljevic
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Doores
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wormald
authors.forename: Angelina S
authors.initials: AS
authors.lastname: Palma
authors.forename: Ten
authors.initials: T
authors.lastname: Feizi
authors.forename: David J
authors.initials: DJ
authors.lastname: Harvey
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Max
authors.initials: M
authors.lastname: Crispin
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Scanlan
mesh_terms: D057134:Antibodies, Neutralizing; D000939:Epitopes / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D008358:Mannose / Q000276:immunology* / Q000378:metabolism; D018716:Molecular Mimicry / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D008358:Mannose