Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site

PLoS Pathogens

Kristin Narayan¹  Joanne Destefano¹  John R. Mascola¹  Xiaoxing Huang²  Janelle Muranaka²  Krisha McKee³  Nicole Doria-Rose³  Sergey Menis⁴  James M. Binley⁴  Bimal Chakrabarti⁴  Keiko Osawa⁴  James E. Robinson⁵  Celia LaBranche⁶  Daniel Kulp⁷  Robert G. Whalen⁷  Tommy Tong⁸  Ema T. Crooks⁸  Guillaume Stewart-Jones⁸  Sean X. Du⁹  Peter D. Kwong^1,10  David C. Montefiori^1,10  Sijy O’Dell^1,10  William R. Schief^1,10  Ping Zhu^1,10  Richard T. Wyatt^1,10  Ivelin S. Georgiev^1,10 

[1] Altravax, Inc., Sunnyvale, California, United States of America;Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America;Department of Surgery, Duke University, Duke University Medical Center, Durham, North Carolina, United States of America;International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at The Scripps Research Institute, Department of Immunology and Microbial Science, La Jolla, California, United States of America;International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America;MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, United Kingdom;National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China;San Diego Biomedical Research Institute, San Diego, California, United States of America;Tulane National Primate Research Center, Covington, Louisiana, United States of America;Vaccine Research Center, National Institutes of Health (NIH), Bethesda, Maryland, United States of America

关键词: Rabbits;    Vaccines;    Antibodies;    Antigens;    Guinea pigs;    HIV-1;    Adsorption;    Proteases;   

DOI  :  10.1371/journal.ppat.1004932

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Eliciting broad tier 2 neutralizing antibodies (nAbs) is a major goal of HIV-1 vaccine research. Here we investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit nAbs. Unusually potent nAb titers developed in 2 of 8 rabbits immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and in 1 of 20 rabbits immunized with DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. Specifically, trimer VLP sera took advantage of the unusual absence of a glycan at residue 197 (present in 98.7% of Envs). Intriguingly, removing the N197 glycan (with no loss of tier 2 phenotype) rendered 50% or 16.7% (n = 18) of clade B tier 2 isolates sensitive to the two trimer VLP sera, showing broad neutralization via the surface masked by the N197 glycan. Neutralizing sera targeted epitopes that overlap with the CD4 binding site, consistent with the role of the N197 glycan in a putative “glycan fence” that limits access to this region. A bioinformatics analysis suggested shared features of one of the trimer VLP sera and monoclonal antibody PG9, consistent with its trimer-dependency. The neutralizing DNA trimer serum took advantage of the absence of a glycan at residue 230, also proximal to the CD4 binding site and suggesting an epitope similar to that of monoclonal antibody 8ANC195, albeit lacking tier 2 breadth. Taken together, our data show for the first time that strain-specific holes in the glycan fence can allow the development of tier 2 neutralizing antibodies to native spikes. Moreover, cross-neutralization can occur in the absence of protecting glycan. Overall, our observations provide new insights that may inform the future development of a neutralizing antibody vaccine.

【 授权许可】

CC BY