Cooperation between somatic mutation and germline-encoded residues enables antibody recognition of HIV-1 envelope glycans Journal Article
| Authors: | Wu, N. R.; Nicely, N. I.; Lee, E. M.; Reed, R. K.; Watts, B. E.; Cai, F.; Walkowicz, W. E.; Aussedat, B.; Jones, J. A.; Eaton, A.; Trama, A. M.; Alam, S. M.; Montefiori, D. C.; Haynes, B. F.; Saunders, K. O. |
| Article Title: | Cooperation between somatic mutation and germline-encoded residues enables antibody recognition of HIV-1 envelope glycans |
| Abstract: | Viral glycoproteins are a primary target for host antibody responses. However, glycans on viral glycoproteins can hinder antibody recognition since they are self glycans derived from the host biosynthesis pathway. During natural HIV-1 infection, neutralizing antibodies are made against glycans on HIV-1 envelope glycoprotein (Env). However, such antibodies are rarely elicited with vaccination. Previously, the vaccine-induced, macaque antibody DH501 was isolated and shown to bind to high mannose glycans on HIV-1 Env. Understanding how DH501 underwent affinity maturation to recognize glycans could inform vaccine induction of HIV-1 glycan antibodies. Here, we show that DH501 Env glycan reactivity is mediated by both germline-encoded residues that contact glycans, and somatic mutations that increase antibody paratope flexibility. Only somatic mutations in the heavy chain were required for glycan reactivity. The paratope conformation was fragile as single mutations within the immunoglobulin fold or complementarity determining regions were sufficient for eliminating antibody function. Taken together, the initial germline VHDJH rearrangement generated contact residues capable of binding glycans, and somatic mutations were required to form a flexible paratope with a cavity conducive to HIV-1 envelope glycan binding. The requirement for the presence of most somatic mutations across the heavy chain variable region provides one explanation for the difficulty in inducing anti-Env glycan antibodies with HIV-1 Env vaccination. © 2019 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| Keywords: | controlled study; somatic mutation; nonhuman; polymerase chain reaction; immunoglobulin; gene rearrangement; genetic transfection; immunoglobulin g; antibody response; antigen recognition; vaccination; crystal structure; virus replication; antigen binding; site directed mutagenesis; transition temperature; surface plasmon resonance; thermostability; human immunodeficiency virus 1; redundancy analysis; proline; crystallography; virion; microsphere; virus glycoprotein; virus neutralization; germline mutation; glycan; differential scanning calorimetry; size exclusion chromatography; antibody combining site; virus envelope; mannose; heavy chain; human; article; ic50; immunoglobulin production; glycoprotein gp 140; kifunensine; mannose oligosaccharide |
| Journal Title: | PLoS Pathogens |
| Volume: | 15 |
| Issue: | 12 |
| ISSN: | 1553-7366 |
| Publisher: | Public Library of Science |
| Date Published: | 2019-12-16 |
| Start Page: | e1008165 |
| Language: | English |
| DOI: | 10.1371/journal.ppat.1008165 |
| PUBMED: | 31841553 |
| PROVIDER: | scopus |
| PMCID: | PMC6936856 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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