Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity
Margaret E. Ackerman, … , Chris Scanlan, Galit Alter
Margaret E. Ackerman, … , Chris Scanlan, Galit Alter
Published April 8, 2013
Citation Information: J Clin Invest. 2013;123(5):2183-2192. https://doi.org/10.1172/JCI65708.
View: Text | PDF
Research Article Immunology

Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity

Abstract

While the induction of a neutralizing antibody response against HIV remains a daunting goal, data from both natural infection and vaccine-induced immune responses suggest that it may be possible to induce antibodies with enhanced Fc effector activity and improved antiviral control via vaccination. However, the specific features of naturally induced HIV-specific antibodies that allow for the potent recruitment of antiviral activity and the means by which these functions are regulated are poorly defined. Because antibody effector functions are critically dependent on antibody Fc domain glycosylation, we aimed to define the natural glycoforms associated with robust Fc-mediated antiviral activity. We demonstrate that spontaneous control of HIV and improved antiviral activity are associated with a dramatic shift in the global antibody-glycosylation profile toward agalactosylated glycoforms. HIV-specific antibodies exhibited an even greater frequency of agalactosylated, afucosylated, and asialylated glycans. These glycoforms were associated with enhanced Fc-mediated reduction of viral replication and enhanced Fc receptor binding and were consistent with transcriptional profiling of glycosyltransferases in peripheral B cells. These data suggest that B cell programs tune antibody glycosylation actively in an antigen-specific manner, potentially contributing to antiviral control during HIV infection.

Authors

Margaret E. Ackerman, Max Crispin, Xiaojie Yu, Kavitha Baruah, Austin W. Boesch, David J. Harvey, Anne-Sophie Dugast, Erin L. Heizen, Altan Ercan, Ickwon Choi, Hendrik Streeck, Peter A. Nigrovic, Chris Bailey-Kellogg, Chris Scanlan, Galit Alter

×

Figure 1

Effector function and global antibody glycosylation profiles.

Options: View larger image (or click on image) Download as PowerPoint
Effector function and global antibody glycosylation profiles. (A) Antibo...
(A) Antibodies from HIV-infected subjects were examined for their ability to inhibit viral replication via neutralization (AB) or ability to recruit NK cells as effectors (NK + AB) in an ADCVI assay. Colored bars correspond to unique glycan structures. (B) NK cell degranulation (dot plot) and cytokine secretion were determined in the ADCVI assay. Pie charts depict the polyfunctional profile of antibody-mediated NK cell recruitment, including degranulating NK cells (CD107a, 1 function), IFN-γ secretion plus degranulation (2 functions), or IFN-γ plus TNF-α plus degranulation (3 functions). (C) Glycan dependence of ADCVI activity. Removal of antibody glycan with the endoglycosidase PNGaseF did not affect neutralization (AB), but ablated viral inhibition resulting from recruitment of NK cells as effectors (AB+). (A–C) Individual symbols represent each subject tested, and horizontal lines represent the median for a given group of clinically related subjects. (D) Global plasma IgG glycosylation profiles for all glycan structures (first panel), galactose content (second panel), and fucose content (third panel). neg, healthy controls; acute, acutely HIV-infected subjects; untx, untreated chronic progressors; tx, treated chronic progressors; ctr, controllers; F, fucosylated; nonF, nonfucosylated.