Cooperation between somatic mutation and germline-encoded residues enables antibody recognition of HIV-1 envelope glycans

Wu, Nelson R.; Nicely, Nathan I.; Lee, Esther M.; Reed, Rachel K.; Watts, Brian E.; Cai, Fangping; Walkowicz, William E.; Aussedat, Baptiste; Jones, Julia A.; Eaton, Amanda; Trama, Ashley M.; Alam, S. Munir; Montefiori, David C.; Haynes, Barton F.; Saunders, Kevin O.

doi:10.1371/journal.ppat.1008165

Title: Cooperation between somatic mutation and germline-encoded residues enables antibody recognition of HIV-1 envelope glycans

Journal Article · Mon Dec 16 00:00:00 UTC 2019 · PLoS Pathogens

DOI: https://doi.org/10.1371/journal.ppat.1008165 · OSTI ID:1854209

^[1];

^[1]; Lee, Esther M. ^[1]; Reed, Rachel K. ^[1]; Watts, Brian E. ^[1]; Cai, Fangping ^[1];

^[2];

^[1];

^[1]; Trama, Ashley M. ^[1]; Alam, S. Munir ^[1];

^[1]; Haynes, Barton F. ^[1];

^[1]

Duke Univ., Durham, NC (United States). Medical Center
Memorial Sloan Kettering Cancer Center, New York, NY (United States)

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 V_HDJ_H 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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1854209

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 12 Vol. 15; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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