title: Mining the antibodyome for HIV-1-neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains.
abstract: Next-generation sequencing of antibody transcripts from HIV-1-infected individuals with broadly neutralizing antibodies could provide an efficient means for identifying somatic variants and characterizing their lineages. Here, we used 454 pyrosequencing and identity/divergence grid sampling to analyze heavy- and light-chain sequences from donor N152, the source of the broadly neutralizing antibody 10E8. We identified variants with up to 28% difference in amino acid sequence. Heavy- and light-chain phylogenetic trees of identified 10E8 variants displayed similar architectures, and 10E8 variants reconstituted from matched and unmatched phylogenetic branches displayed significantly lower autoreactivity when matched. To test the generality of phylogenetic pairing, we analyzed donor International AIDS Vaccine Initiative 84, the source of antibodies PGT141-145. Heavy- and light-chain phylogenetic trees of PGT141-145 somatic variants also displayed remarkably similar architectures; in this case, branch pairings could be anchored by known PGT141-145 antibodies. Altogether, our findings suggest that phylogenetic matching of heavy and light chains can provide a means to approximate natural pairings.
authors.affiliation: Vaccine Research Center, National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.forename: Gilad
authors.initials: G
authors.lastname: Ofek
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.forename: Baoshan
authors.initials: B
authors.lastname: Zhang
authors.forename: Mark K
authors.initials: MK
authors.lastname: Louder
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lu
authors.forename: Krisha
authors.initials: K
authors.lastname: McKee
authors.forename: Marie
authors.initials: M
authors.lastname: Pancera
authors.forename: Jeff
authors.initials: J
authors.lastname: Skinner
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Zhang
authors.forename: Robert
authors.initials: R
authors.lastname: Parks
authors.forename: Joshua
authors.initials: J
authors.lastname: Eudailey
authors.forename: Krissey E
authors.initials: KE
authors.lastname: Lloyd
authors.forename: Julie
authors.initials: J
authors.lastname: Blinn
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Melissa
authors.initials: M
authors.lastname: Simek
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Koff
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
mesh_terms: D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000235:genetics*; D019295:Computational Biology; D030541:Databases, Genetic; D004797:Enzyme-Linked Immunosorbent Assay; D015497:HIV-1 / Q000276:immunology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010802:Phylogeny; D016415:Sequence Alignment
chemical_list: D057134:Antibodies, Neutralizing; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains
references.citation: Nat Med. 2007 Sep;13(9):1032-4
references.pmid: 17721546
references.citation: Science. 2011 Sep 16;333(6049):1593-602
references.pmid: 21835983
references.citation: Front Microbiol. 2012 Sep 11;3:315
references.pmid: 23024643
references.citation: Science. 2012 Jul 13;337(6091):183-6
references.pmid: 22798606
references.citation: Science. 2011 Sep 16;333(6049):1633-7
references.pmid: 21764753
references.citation: BMC Res Notes. 2011 Oct 12;4:404
references.pmid: 21992227
references.citation: MAbs. 2011 Jan-Feb;3(1):17-20
references.pmid: 21099370
references.citation: Nat Biotechnol. 2012 Mar 25;30(5):447-52
references.pmid: 22446692
references.citation: Nat Biotechnol. 2010 Sep;28(9):965-9
references.pmid: 20802495
references.citation: Nature. 2011 Sep 22;477(7365):466-70
references.pmid: 21849977
references.citation: Clin Exp Immunol. 1988 Nov;74(2):247-53
references.pmid: 3224443
references.citation: Immunity. 2012 Sep 21;37(3):412-25
references.pmid: 22999947
references.citation: Science. 2009 May 8;324(5928):807-10
references.pmid: 19423829
references.citation: J Virol. 2012 Aug;86(15):8319-23
references.pmid: 22623764
references.citation: Nature. 1988 Aug 25;334(6184):676-82
references.pmid: 3261841
references.citation: Science. 2005 Jun 24;308(5730):1906-8
references.pmid: 15860590
references.citation: J Virol. 2009 Jul;83(14):7337-48
references.pmid: 19439467
references.citation: Nature. 2012 Nov 15;491(7424):406-12
references.pmid: 23151583
references.citation: Nature. 2009 Apr 2;458(7238):636-40
references.pmid: 19287373
references.citation: Nucleic Acids Res. 2010 Nov;38(21):e193
references.pmid: 20846958
references.citation: Science. 2009 Oct 9;326(5950):285-9
references.pmid: 19729618
references.citation: Nat Immunol. 2009 Jun;10(6):573-8
references.pmid: 19448659
references.citation: Nature. 2011 Nov 23;480(7377):336-43
references.pmid: 22113616
references.citation: J Exp Med. 1981 Apr 1;153(4):897-909
references.pmid: 6972993
references.citation: Arthritis Rheum. 1994 Oct;37(10):1453-61
references.pmid: 7945470
references.citation: Hum Antibodies. 2005;14(3-4):59-67
references.pmid: 16720975
references.citation: Curr Opin Biotechnol. 2011 Aug;22(4):584-9
references.pmid: 21570821
references.citation: J Virol. 2008 Dec;82(23):11651-68
references.pmid: 18815292
references.citation: Science. 2010 Aug 13;329(5993):856-61
references.pmid: 20616233