title: The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies.
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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America ; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, 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.
authors.forename: Devin
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authors.lastname: Sok
authors.forename: Uri
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authors.lastname: Laserson
authors.forename: Jonathan
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authors.lastname: Laserson
authors.forename: Yi
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authors.lastname: Liu
authors.forename: Francois
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authors.lastname: Vigneault
authors.forename: Jean-Philippe
authors.initials: JP
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authors.forename: Bryan
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authors.lastname: Briney
authors.forename: Alejandra
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authors.lastname: Ramos
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authors.forename: Khoa
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authors.lastname: Le
authors.forename: Alison
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authors.lastname: Mahan
authors.forename: Shenshen
authors.initials: S
authors.lastname: Wang
authors.forename: Mehran
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authors.lastname: Kardar
authors.forename: Gur
authors.initials: G
authors.lastname: Yaari
authors.forename: Laura M
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authors.lastname: Walker
authors.forename: Birgitte B
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authors.lastname: Simen
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: St John
authors.forename: Po-Ying
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authors.lastname: Chan-Hui
authors.forename: Kristine
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authors.lastname: Swiderek
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Kleinstein
authors.forename: Galit
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authors.lastname: Alter
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Arup K
authors.initials: AK
authors.lastname: Chakraborty
authors.forename: Daphne
authors.initials: D
authors.lastname: Koller
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: George M
authors.initials: GM
authors.lastname: Church
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Pascal
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authors.lastname: Poignard
mesh_terms: D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male; D011134:Polysaccharides / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011134:Polysaccharides; C514793:gp120 protein, Human immunodeficiency virus 1