The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies.

TitleThe effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies.
Publication TypeJournal Article
Year of Publication2013
AuthorsSok D, Laserson U, Laserson J, Liu Y, Vigneault F, Julien J-P, Briney B, Ramos A, Saye KF, Le K, Mahan A, Wang S, Kardar M, Yaari G, Walker LM, Simen BB, St John EP, Chan-Hui P-Y, Swiderek K, Kleinstein SH, Kleinstein SH, Alter G, Seaman MS, Chakraborty AK, Koller D, Wilson IA, Church GM, Burton DR, Poignard P
JournalPLoS Pathog
Volume9
Issue11
Paginatione1003754
Date Published11/21/2013
ISSN1553-7374
Abstract

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.

DOI10.1371/journal.ppat.1003754
Alternate JournalPLoS Pathog.
PubMed ID24278016
PubMed Central IDPMC3836729
Grant List1U19AI090970 / AI / NIAID NIH HHS / United States
5T32AI007606-10 / AI / NIAID NIH HHS / United States
AI84817 / AI / NIAID NIH HHS / United States
NIH R01AI033292 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
Y1-CO-1020 / CO / NCI NIH HHS / United States
Y1-GM-1104 / GM / NIGMS NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
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