Visualization of the HIV-1 Env glycan shield across scales

Berndsen, Zachary T.; Chakraborty, Srirupa; Wang, Xiaoning; Cottrell, Christopher A.; Torres, Jonathan L.; Diedrich, Jolene K.; López, Cesar A.; Yates III, John R.; van Gils, Marit J.; Paulson, James C.; Gnanakaran, Sandrasegaram; Ward, Andrew B.

doi:10.1073/pnas.2000260117

Title: Visualization of the HIV-1 Env glycan shield across scales

Journal Article · Thu Oct 22 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2000260117· OSTI ID:1762730

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^[1]; Diedrich, Jolene K. ^[1];

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^[1]; van Gils, Marit J. ^[3];

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The Scripps Research Inst., La Jolla, CA (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Univ. of Amsterdam (Netherlands)

The dense array of N-linked glycans on the HIV-1 envelope glycoprotein (Env), known as the “glycan shield,” is a key determinant of immunogenicity, yet intrinsic heterogeneity confounds typical structure–function analysis. Here, we present an integrated approach of single-particle electron cryomicroscopy (cryo-EM), computational modeling, and site-specific mass spectrometry (MS) to probe glycan shield structure and behavior at multiple levels. We found that dynamics lead to an extensive network of interglycan interactions that drive the formation of higher-order structure within the glycan shield. This structure defines diffuse boundaries between buried and exposed protein surface and creates a mapping of potentially immunogenic sites on Env. Analysis of Env expressed in different cell lines revealed how cryo-EM can detect subtle changes in glycan occupancy, composition, and dynamics that impact glycan shield structure and epitope accessibility. Importantly, this identified unforeseen changes in the glycan shield of Env obtained from expression in the same cell line used for vaccine production. Finally, by capturing the enzymatic deglycosylation of Env in a time-resolved manner, we found that highly connected glycan clusters are resistant to digestion and help stabilize the prefusion trimer, suggesting the glycan shield may function beyond immune evasion.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); Bill and Melinda Gates Foundation

Grant/Contract Number:: 89233218CNA000001; UM1 AI100663; UM1 AI144462; AI113867; P41GM103533; OPP1100639; OPP1115782; OPP1196345/INV-008813; UM1 AI100645; UM1 AI144371

OSTI ID:: 1762730

Report Number(s):: LA-UR-19-30964

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Issue 45; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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Quantification of the Resilience and Vulnerability of HIV-1 Native Glycan Shield at Atomistic Detail Chakraborty, Srirupa; Berndsen, Zachary T.; Hengartner, Nicolas W. SSRN Electronic Journal https://doi.org/10.2139/ssrn.3606299	journal	January 2020

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