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222 Antibody 2G12 recognizes a glycopeptide epitope on HIV-1 gp120 envelope glycoprotein

Huang, Wei; Lewis, George K; Wang, Lai-Xi

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JAIDS Journal of Acquired Immune Deficiency Syndromes: June 2009 - Volume 51 - Issue -
doi: 10.1097/01.qai.0000351178.71714.b5
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Identification of novel neutralizing epitope on HIV-1 envelope glycoproteins is an essential step toward developing an effective HIV-1 vaccine. Human antibody 2G12 is one of the few broadly neutralizing antibodies capable of neutralizing a range of HIV-1 primary isolates. Previous studies have suggested that 2G12 recognizes a carbohydrate antigen involving several N-glycans that form a novel oligosaccharide cluster. The two N-glycans at the base of the V3 loop, N295 and N332, seem to be essential as mutation of any of them will diminish gp120's binding to 2G12. The role of the V3 domain is still unclear although mutational studied implicated that V3 might not be involved in 2G12 recognition. Using a chemoenzymatic approach, we have synthesized the full-size V3 domain glycopeptide, in which the two N-glycans at N295 and N332 were assembled in the context of the V3 domain. Our 2G12-binding results implicate that the V3 polypeptide not only provided a scaffold to hold the carbohydrate cluster, but was also involved in the interaction with 2G12. Thus, we propose that a unique HIV-1 V3 glycopeptide constitutes the epitope for antibody 2G12. A molecular modeling study with 2G12 and the synthetic antigen supports this notion. This discovery provides insights into the mechanism of 2G12-mediated recognition and neutralization, which will facilitate the design of a glycopeptide-based HIV-1 vaccine.

© 2009 Lippincott Williams & Wilkins, Inc.