期刊
JOURNAL OF IMMUNOLOGY
卷 185, 期 11, 页码 6876-6882出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1002600
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资金
- Fonds zur Forderung der Wissenschaftlichen Forschung [P18314, J2845-B13, L575-B13]
- U.S. Public Health Service [R21AI078477]
- Austrian Science Fund (FWF) [P18314] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [L 575] Funding Source: researchfish
Interactions between the Fc segment of IgG and Fc gamma Rs on a variety of cells are likely to play an important role in the anti-HIV activity of Abs. Because the nature of the glycan structure on the Fc domain is a critical determinant of Fc-Fc gamma R binding, proper Fc glycosylation may contribute to Ab-mediated protection. We have generated five different glycoforms of the broadly HIV-1-neutralizing mAb 2G12 in wild-type and glycoengineered plants and Chinese hamster ovary cells. Plant-derived 2G12 exhibited highly homogeneous glycosylation profiles with a single dominant N-glycan species. Using flow cytometry with Fc gamma R-expressing-cell lines, all 2G12 glycoforms demonstrated similar binding to Fc gamma RI, Fc gamma RIIa, and Fc gamma RIIb. In contrast, two glycoforms derived from glycoengineered plants that lack plant-specific xylose and core alpha 1,3-fucose, and instead carry human-like glycosylation with great uniformity, showed significantly enhanced binding to Fc gamma RIIIa compared with Chinese hamster ovary or wild-type plant-derived 2G12. Using surface plasmon resonance, we show that binding of 2G12 to Fc gamma RIIIa is markedly affected by core fucose, irrespective of its plant-specific alpha 1,3 or mammalian-type alpha 1,6 linkage. Consistent with this finding, 2G12 glycoforms lacking core fucose (and xylose) mediated higher antiviral activity against HIV-1 or simian immunodeficiency virus as measured by Ab-dependent cell-mediated virus inhibition. This is, to our knowledge, the first demonstration that specific alterations of Fc glycosylation can improve antiviral activity. Such alterations may result in better immunotherapeutic reagents. Moreover, biasing vaccine-induced immune responses toward optimal Fc glycosylation patterns could result in improved vaccine efficacy. The Journal of Immunology, 2010, 185: 6876-6882.
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