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PGT121GM: Several antibodies including 10-1074 were isolated from B-cell clone encoding PGT121, from a clade A-infected African donor using YU-2 gp140 trimers as bait. These antibodies were segregated into PGT121-like (PGT121-123 and 9 members) and 10-1074-like (20 members) groups distinguished by sequence, binding affinity, carbohydrate recognition, neutralizing activity, the V3 loop binding and the role of glycans in epitope formation. The epitopes for both groups contain a potential N-linked glycosylation site (PNGS) at Asn332gp120 and the base of the V3 loop of the gp120 subunit of the HIV spike. However, the 10-1074–like Abs required an intact PNGS at Asn332gp120 for their neutralizing activity, whereas PGT121-like antibodies were able to neutralize some viral strains lacking the Asn332gp120 PNGS. To evaluate the contributions of complex-type N-glycan contacting residues identified from the liganded PGT121 structure, two glycomutant mutant antibodies were designed to exchange the complex-type glycan-contacting residues between PGT121 and 10- 1074: a 10-1074GM IgG with PGT121 residues (six substitutions in IgH: Y32S, D53K, R54S, T58N, R97H, and Y100lT) and a PGT121GM IgG with reciprocal substitutions. PGT121GM and 10-1074GM exhibited near–wild-type affinity for YU-2 gp120/gp140, but had no glycan binding. Both mutants neutralized the YU-2 virus; however, 64% of the PGT121-sensitive strains were resistant to PGT121GM, suggesting that the glycan-contacting residues identified in the liganded PGT121 structure are relevant to the neutralization activity of PGT121. Conversely, 10-1074GM exhibited a higher average potency than wild-type 10-1074 against the 10-1074–sensitive strains, including potency increases of more than threefold against four 10-1074–sensitive strains.
Mouquet2012a
(antibody generation, glycosylation, neutralization, binding affinity)
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Isolation Paper
Mouquet2012a
Hugo Mouquet, Louise Scharf, Zelda Euler, Yan Liu, Caroline Eden, Johannes F. Scheid, Ariel Halper-Stromberg, Priyanthi N. P. Gnanapragasam, Daniel I. R. Spencer, Michael S. Seaman, Hanneke Schuitemaker, Ten Feizi, Michel C. Nussenzweig, and Pamela J. Bjorkman. Complex-Type N-Glycan Recognition by Potent Broadly Neutralizing HIV Antibodies. Proc. Natl. Acad. Sci. U.S.A, 109(47):E3268-E3277, 20 Nov 2012. PubMed ID: 23115339.
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