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

PLoS Pathogens

Celia C. LaBranche¹  Tongqing Zhou²  James Peacock³  Andrew T. McGuire⁴  Shay Behrens⁵  Quentin J. Sattentau⁶  Matthew D. Gray⁷ 

[1]Department of Surgery, Duke University Medical Center, Durham, NC, United States of America

[2]Duke University School of Medicine, Departments of Medicine and Immunology, Duke Human Vaccine Institute, Durham, NC, United States of America

[3]Emory University, UNITED STATES

[4]Fred Hutchinson Cancer Research Center, Department of Global Health, Seattle, WA, United States of America

[5]The Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom

[6]University of Washington, Department of Global Health, Seattle, Washington, United States of America

[7]Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

DOI  :  10.1371/journal.ppat.1007431

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY