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.

AIDS and Cancer Virus Program Frederick National Laboratory for Cancer Research Frederick MD USA

Department of Biochemistry and Molecular Genetics University of Alabama at Birmingham Birmingham AL USA

Department of Immunology Palacky University Olomouc Olomouc Czech Republic

Department of Medicine University of Alabama at Birmingham Birmingham AL USA

Department of Microbiology University of Alabama at Birmingham 845 19th Street S Birmingham AL 35294 USA

Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD USA

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Beyond glycan barriers: non-cognate ligands and protein mimicry approaches to elicit broadly neutralizing antibodies for HIV-1