Journal of Molecular Biology
CommunicationInhibition of Mammalian Glycan Biosynthesis Produces Non-self Antigens for a Broadly Neutralising, HIV-1 Specific Antibody
Section snippets
2G12 can cross-react with “self” carbohydrates, in a “non-self” arrangement
The surface of HIV is decorated entirely with host cell-derived carbohydrates.24 Therefore, a fundamental question in the design of a carbohydrate vaccine for HIV-1 is how a self antigen, such as Man9GlcNAc2, can be recognised on the surface of HIV but not on host cells. Although not abundant, oligomannose glycans are found on host protein surfaces, probably as a result of sterically obscured glycosylation,25 yet 2G12 exhibits no known autoreactivity. We have previously suggested that 2G12
Recombinant mimics of 2G12 epitope of gp120
The results obtained from 293T cells suggest that unusual clustering of self carbohydrates is sufficient for non-self recognition. To investigate this phenomenon at at a molecular level, we recombinantly expressed a known, heavily glycosylated glycoprotein, CEACAM1 in the presence of kifunensine (20 μM). The extracellular domain of CEACAM1 is 120 kDa and, like gp120, is approximately 50% carbohydrate by mass.27., 28., [29], [30] The effect of kifunensine treatment on the 15 N-linked
Glycan modification leads to increased antigenicity of gp120 for 2G12
The results from this study may be generalised to any sufficiently glycosylated protein including, for example, gp120. Our results show that expression of gp120 in the presence of kifunensine increases both the apparent binding (Figure 4(a)) and, interestingly, the valency of gp120 for 2G12 (Figure 4(b)). The kifunensine-derived gp120 (gp120kif) binds more than one 2G12 antibody: to our knowledge, this represents the first report of a gp120 modification that results in an additional binding
References (36)
- et al.
Relevance of the antibody response against human immunodeficiency virus type 1 envelope to vaccine design
Immunol. Letters
(1997) - et al.
Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41
Immunity
(2005) - et al.
Antibody protection: passive immunization of neonates against oral AIDS virus challenge
Vaccine
(2003) - et al.
Structural basis for catalysis and inhibition of N-glycan processing class I alpha 1,2-mannosidases
J. Biol. Chem.
(2000) - et al.
A rapid high-resolution high-performance liquid chromatographic method for separating glycan mixtures and analyzing oligosaccharide profiles
Anal. Biochem.
(1996) - et al.
Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection
Proc. Natl Acad. Sci. USA
(2005) - et al.
Antibody neutralization and escape by HIV-1
Nature
(2003) - et al.
The neutralizing antibody response to HIV-1: viral evasion and escape from humoral immunity
Aids
(1999) - et al.
Antibody vs. HIV in a clash of evolutionary titans
Proc. Natl Acad. Sci. USA
(2005) - et al.
Neutralizing antibody responses against autologous and heterologous viruses in acute versus chronic human immunodeficiency virus (HIV) infection: evidence for a constraint on the ability of HIV to completely evade neutralizing antibody responses
J. Virol.
(2006)
GP120: target for neutralizing HIV-1 antibodies
Annu. Rev. Immunol.
Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1
J. Virol.
Structural definition of a conserved neutralization epitope on HIV-1 gp120
Nature
Antibody domain exchange is an immunological solution to carbohydrate cluster recognition
Science
Comprehensive cross-clade neutralization analysis of a panel of anti-human immunodeficiency virus type 1 monoclonal antibodies
J. Virol.
Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41
J. Virol.
Anti-human immunodeficiency virus type 1 (HIV-1) antibodies 2F5 and 4E10 require surprisingly few crucial residues in the membrane-proximal external region of glycoprotein gp41 to neutralize HIV-1
J. Virol.
Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope
J. Virol.
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These two authors contributed equally to this work.