Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16

Marie Pancera, Syed Shahzad-Ul-Hussan, Nicole A. Doria-Rose, Jason S. McLellan, Robert T. Bailer, Kaifan Dai, Sandra Loesgen, Mark K. Louder, Ryan P. Staupe, Yongping Yang, Baoshan Zhang, Robert Parks, Joshua Eudailey, Krissey E. Lloyd, Julie Blinn, S. Munir Alam, Barton F. Haynes, Mohammed N. Amin, Lai Xi Wang, Dennis R. BurtonWayne C. Koff, Gary J. Nabel, John R. Mascola, Carole A. Bewley, Peter D. Kwong

Research output: Contribution to journalArticle

Abstract

HIV-1 uses a diverse N-linked-glycan shield to evade recognition by antibody. Select human antibodies, such as the clonally related PG9 and PG16, recognize glycopeptide epitopes in the HIV-1 V1-V2 region and penetrate this shield, but their ability to accommodate diverse glycans is unclear. Here we report the structure of antibody PG16 bound to a scaffolded V1-V2, showing an epitope comprising both high mannose-type and complex-type N-linked glycans. We combined structure, NMR and mutagenesis analyses to characterize glycan recognition by PG9 and PG16. Three PG16-specific residues, arginine, serine and histidine (RSH), were critical for binding sialic acid on complex-type glycans, and introduction of these residues into PG9 produced a chimeric antibody with enhanced HIV-1 neutralization. Although HIV-1-glycan diversity facilitates evasion, antibody somatic diversity can overcome this and can provide clues to guide the design of modified antibodies with enhanced neutralization.

Original languageEnglish (US)
Pages (from-to)804-813
Number of pages10
JournalNature structural & molecular biology
Volume20
Issue number7
DOIs
StatePublished - Jul 2013
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Pancera, M., Shahzad-Ul-Hussan, S., Doria-Rose, N. A., McLellan, J. S., Bailer, R. T., Dai, K., Loesgen, S., Louder, M. K., Staupe, R. P., Yang, Y., Zhang, B., Parks, R., Eudailey, J., Lloyd, K. E., Blinn, J., Alam, S. M., Haynes, B. F., Amin, M. N., Wang, L. X., ... Kwong, P. D. (2013). Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16. Nature structural & molecular biology, 20(7), 804-813. https://doi.org/10.1038/nsmb.2600