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HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies

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Item Type:Article
Title:HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies
Creators Name:LaBranche, C.C. and McGuire, A.T. and Gray, M.D. and Behrens, S. and Chen, X. and Zhou, T. and Sattentau, Q.J. and Peacock, J. and Eaton, A. and Greene, K. and Gao, H. and Tang, H. and Perez, L.G. and Saunders, K.O. and Kwong, P.D. and Mascola, J.R. and Haynes, B.F. and Stamatatos, L. and Montefiori, D.C.
Abstract:Broadly neutralizing antibody (bnAb) induction is a high priority for effective HIV-1 vaccination. VRC01-class bnAbs that target the CD4 binding site (CD4bs) of trimeric HIV-1 envelope (Env) glycoprotein spikes are particularly attractive to elicit because of their extraordinary breadth and potency of neutralization in vitro and their ability to protect against infection in animal models. Glycans bordering the CD4bs impede the binding of germline-reverted forms of VRC01-class bnAbs and therefore constitute a barrier to early events in initiating the correct antibody lineages. Deleting a subset of these glycans permits Env antigen binding but not virus neutralization, suggesting that additional barriers impede germline-reverted VRC01-class antibody binding to functional Env trimers. We investigated the requirements for functional Env trimer engagement of VRC01-class naïve B cell receptors by using virus neutralization and germline-reverted antibodies as surrogates for the interaction. Targeted deletion of a subset of N-glycans bordering the CD4bs, combined with Man5 enrichment of remaining N-linked glycans that are otherwise processed into larger complex-type glycans, rendered HIV-1 426c Env-pseudotyped virus (subtype C, transmitted/founder) highly susceptible to neutralization by near germline forms of VRC01-class bnAbs. Neither glycan modification alone rendered the virus susceptible to neutralization. The potency of neutralization in some cases rivaled the potency of mature VRC01 against wildtype viruses. Neutralization by the germline-reverted antibodies was abrogated by the known VRC01 resistance mutation, D279K. These findings improve our understanding of the restrictions imposed by glycans in eliciting VRC01-class bnAbs and enable a neutralization-based strategy to monitor vaccine-elicited early precursors of this class of bnAbs.
Keywords:B-Lymphocytes, Binding Sites, Broadly Neutralizing Antibodies, CD4 Antigens, Epitopes, Glycosylation, HIV Antibodies, HIV Envelope Protein gp120, HIV Infections, HIV Seropositivity, HIV-1, Human Immunodeficiency Virus env Gene Products, Monoclonal Antibodies, Neutralizing Antibodies, Polysaccharides
Source:PLoS Pathogens
Publisher:Public Library of Science
Page Range:e1007431
Date:5 November 2018
Additional Information:Erratum in: PLoS Pathogens 15(3): e1007646.
Official Publication:https://doi.org/10.1371/journal.ppat.1007431
PubMed:View item in PubMed

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