Mining the antibodyome for HIV-1-neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains.

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TitleMining the antibodyome for HIV-1-neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains.
Publication TypeJournal Article
Year of Publication2013
AuthorsZhu, J, Ofek, GA, Yang, Y, Zhang, B, Louder, MK, Lu, G, McKee, K, Pancera, M, Skinner, J, Zhang, Z, Parks, R, Eudailey, J, Lloyd, KE, Blinn, J, S Alam, M, Haynes, BF, Simek, M, Burton, DR, Koff, WC, Mullikin, JC, Mascola, JR, Shapiro, L, Kwong, PD
Corporate AuthorsNISC Comparative Sequencing Program
JournalProc Natl Acad Sci U S A
Volume110
Issue16
Pagination6470-5
Date Published2013 Apr 16
ISSN1091-6490
KeywordsAmino Acid Sequence, Antibodies, Neutralizing, Computational Biology, Databases, Genetic, Enzyme-Linked Immunosorbent Assay, High-Throughput Nucleotide Sequencing, HIV-1, Humans, Immunoglobulin Heavy Chains, Immunoglobulin Light Chains, Models, Molecular, Molecular Sequence Data, Neutralization Tests, Phylogeny, Sequence Alignment
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.

DOI10.1073/pnas.1219320110
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23536288
PubMed Central IDPMC3631616
Grant ListUM1 AI100645 / AI / NIAID NIH HHS / United States
/ / Intramural NIH HHS / United States