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

Academic Article
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Overview

authors

  • Zhu, Jiang
  • Ofek, G.
  • Yang, Y. P.
  • Zhang, B. S.
  • Louder, M. K.
  • Lu, G.
  • McKee, K.
  • Pancera, M.
  • Skinner, J.
  • Zhang, Z. H.
  • Parks, R.
  • Eudailey, J.
  • Lloyd, K. E.
  • Blinn, J.
  • Alam, S. M.
  • Haynes, B. F.
  • Simek, M.
  • Burton, Dennis
  • Koff, W. C.
  • NISC Comparative Sequencing Program
  • Mullikin, J. C.
  • Mascola, J. R.
  • Shapiro, L.
  • Kwong, P. D.

publication date

  • April 2013

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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.

subject areas

  • Amino Acid Sequence
  • Antibodies, Neutralizing
  • Computational Biology
  • Databases, Genetic
  • Enzyme-Linked Immunosorbent Assay
  • HIV-1
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Light Chains
  • Models, Molecular
  • Molecular Sequence Data
  • Neutralization Tests
  • Phylogeny
  • Sequence Alignment
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Research

keywords

  • B-cell ontogeny
  • DNA sequencing
  • antibody-affinity maturation
  • antibodyomics
  • immunological tolerance
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Identity

PubMed Central ID

  • PMC3631616

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1219320110

PubMed ID

  • 23536288
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Additional Document Info

start page

  • 6470

end page

  • 6475

volume

  • 110

issue

  • 16

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