Download MendeleyCooperation between somatic mutation and germline-encoded residues enable antibody recognition of HIV-1 envelope glycans.
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.(2019) PLoS Pathog 15: e1008165-e1008165
- PubMed: 31841553
- DOI: https://doi.org/10.1371/journal.ppat.1008165
- Primary Citation of Related Structures:
6P3B - PubMed 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.
Organizational Affiliation:
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
