Glycan Positioning Impacts HIV-1 Env Glycan-Shield Density, Function, and Recognition by Antibodies
Qing Wei, Audra A. Hargett, Barbora Knoppová, Alexandra Duverger, Reda Rawi, Chen‐Hsiang Shen, S. Katie Farney, Stacy Hall, Rhubell Brown, Brandon F. Keele, Sonya L. Heath, Michael S. Saag, Olaf Kutsch, Gwo‐Yu Chuang, Peter D. Kwong, Zina Moldoveanu, Milan Raška, Matthew B. Renfrow, Jan Novák
Abstract
HIV-1 envelope (Env) N-glycosylation impact virus-cell entry and immune evasion. How each glycan interacts to shape the Env-protein-sugar complex and affects Env function is not well understood. Here, analysis of two Env variants from the same donor, with differing functional characteristics and N-glycosylation-site composition, revealed that changes to key N-glycosylation sites affected the Env structure at distant locations and had a ripple effect on Env-wide glycan processing, virus infectivity, antibody recognition, and virus neutralization. Specifically, the N262 glycan, although not in the CD4-binding site, modulated Env binding to the CD4 receptor, affected Env recognition by several glycan-dependent neutralizing antibodies, and altered site-specific glycosylation heterogeneity, with, for example, N448 displaying limited glycan processing. Molecular-dynamic simulations visualized differences in glycan density and how specific oligosaccharide positions can move to compensate for a glycan loss. This study demonstrates how changes in individual glycans can alter molecular dynamics, processing, and function of the Env-glycan shield.