The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies

PLoS Pathogens

Alison Mahan¹  Karen F. Saye²  Bryan Briney³  Alejandra Ramos³  Jean-Philippe Julien⁴  Khoa Le⁴  Devin Sok⁵  Ian A. Wilson⁵  Michael S. Seaman⁵  Po-Ying Chan-Hui⁵  Laura M. Walker⁵  Gur Yaari⁶  Yi Liu⁷  Francois Vigneault⁸  Uri Laserson⁹  Kristine Swiderek⁹  Birgitte B. Simen⁹  George M. Church⁹  Arup K. Chakraborty⁹  Shenshen Wang⁹  Galit Alter^1,10  Pascal Poignard^1,11  Daphne Koller^1,12  Dennis R. Burton^1,12  Jonathan Laserson^1,12  Elizabeth P. St. John^1,12  Mehran Kardar^1,12  Stephen H. Kleinstein^1,12 

[1] AbVitro Inc., Boston, Massachusetts, United States of America;Biomedical Informatics Training Program, Stanford University School of Medicine, Stanford, California, United States of America;Department of Computer Science, Stanford University, Stanford, California, United States of America;Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America;Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America;Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America;Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America;Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America;IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America;International AIDS Vaccine Initiative, New York, New York, United States of America;Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts, United States of America;Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, United States of America

关键词: Antibodies;    Enzyme-linked immunoassays;    Chemical neutralization;    Cloning;    Flow cytometry;    HIV;    Phylogenetics;    Vaccination;    immunization;   

DOI  :  10.1371/journal.ppat.1003754

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Broadly neutralizing HIV antibodies (bnAbs) are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121–134 and found a positive correlation between the level of somatic hypermutation (SHM) and the development of neutralization breadth and potency. Strikingly, putative intermediates were characterized that show approximately half the mutation level of PGT121–134 but were still capable of neutralizing roughly 40–80% of PGT121–134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than PGT121–134. Such antibodies with lower levels of SHM may be more amenable to elicitation through vaccination while still providing noteworthy coverage. Binding characterization indicated a preference of inferred intermediates for native Env binding over monomeric gp120, suggesting that the PGT121–134 lineage may have been selected for binding to native Env at some point during maturation. Analysis of glycan-dependent neutralization for inferred intermediates identified additional adjacent glycans that comprise the epitope and suggests changes in glycan dependency or recognition over the course of affinity maturation for this lineage. Finally, patterns of neutralization of inferred bnAb intermediates suggest hypotheses as to how SHM may lead to potent and broad HIV neutralization and provide important clues for immunogen design.

【 授权许可】

CC BY