Abstract

Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01–12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30–38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Data deposits

Coordinates and structure factors for CAP256-VRC26 lineage Fabs have been deposited with the Protein Data Bank under accession codes 4ODH, 4OCR, 4OD1, 4ORG, 4OCW, 4OD3 and 4OCS. The EM reconstruction density for the CAP256-VRC26.09 complex with BG505 SOSIP.664 trimer has been deposited with the Electron Microscopy Data Bank under accession code EMD-5856. We have also deposited deep sequencing data used in this study to National Center for Biotechnology Information Short Reads Archives (SRA) under accession numbers SRP034555 and SRP017087. Information deposited with GenBank includes: the heavy- and light-chain variable region sequences of cloned antibodies CAP256-VRC26.01-12, UCA, I1 and I2 (accession numbers KJ134860KJ134889); bioinformatically identified VRC26-related sequences from B cell transcripts: 680 heavy chains and 472 light chains (accession numbers KJ133708KJ134387, KJ134388KJ134859); and CAP256 Env sequences (accession numbers KF996576KF996716).

References

  1. 1.

    , , & B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nature Biotechnol. 30, 423–433 (2012)

  2. 2.

    & Antigenicity and immunogenicity in HIV-1 antibody-based vaccine design. J. AIDS Clinic. Res. (Suppl. 8)003 (2012)

  3. 3.

    & HIV-1 neutralizing antibodies: understanding nature's pathways. Immunol. Rev. 254, 225–244 (2013)

  4. 4.

    , , & Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc. Natl Acad. Sci. USA 100, 4144–4149 (2003)

  5. 5.

    et al. Antibody neutralization and escape by HIV-1. Nature 422, 307–312 (2003)

  6. 6.

    et al. The neutralization breadth of HIV-1 develops incrementally over four years and is associated with CD4+ T cell decline and high viral load during acute infection. J. Virol. 85, 4828–4840 (2011)

  7. 7.

    et al. Breadth of neutralizing antibody response to human immunodeficiency virus type 1 is affected by factors early in infection but does not influence disease progression. J. Virol. 83, 10269–10274 (2009)

  8. 8.

    et al. Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection. J. Virol. 83, 757–769 (2009)

  9. 9.

    et al. Breadth of human immunodeficiency virus-specific neutralizing activity in sera: clustering analysis and association with clinical variables. J. Virol. 84, 1631–1636 (2010)

  10. 10.

    et al. Precise determination of the diversity of a combinatorial antibody library gives insight into the human immunoglobulin repertoire. Proc. Natl Acad. Sci. USA 106, 20216–20221 (2009)

  11. 11.

    , , & High-throughput antibody sequencing reveals genetic evidence of global regulation of the naive and memory repertoires that extends across individuals. Genes Immun. 13, 469–473 (2012)

  12. 12.

    et al. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333, 1593–1602 (2011)

  13. 13.

    et al. Mining the antibodyome for HIV-1-neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains. Proc. Natl Acad. Sci. USA 110, 6470–6475 (2013)

  14. 14.

    et al. Somatic populations of PGT135–137 HIV-1-neutralizing antibodies identified by 454 pyrosequencing and bioinformatics. Front. Microbiol. 3, 315 (2012)

  15. 15.

    et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496, 469–476 (2013)

  16. 16.

    et al. A limited number of antibody specificities mediate broad and potent serum neutralization in selected HIV-1 infected individuals. PLoS Pathog. 6, e1001028 (2010)

  17. 17.

    et al. The B cell response is redundant and highly focused on V1V2 during early subtype C infection in a Zambian seroconverter. J. Virol. 85, 905–915 (2011)

  18. 18.

    et al. Delineating antibody recognition in polyclonal sera from patterns of HIV-1 isolate neutralization. Science 340, 751–756 (2013)

  19. 19.

    et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326, 285–289 (2009)

  20. 20.

    et al. Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J. Virol. 85, 9998–10009 (2011)

  21. 21.

    et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011)

  22. 22.

    et al. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480, 336–343 (2011)

  23. 23.

    et al. Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1–V2-directed antibody PG16. Nature Struct. Mol. Biol. 20, 804–813 (2013)

  24. 24.

    et al. Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9. Proc. Natl Acad. Sci. USA 110, 4351–4356 (2013)

  25. 25.

    et al. Potent and broad neutralization of HIV-1 subtype C by plasma antibodies targeting a quaternary epitope including residues in the V2 loop. J. Virol. 85, 3128–3141 (2011)

  26. 26.

    et al. Multiple pathways of escape from HIV broadly cross-neutralizing V2-dependent antibodies. J. Virol. 87, 4882–4894 (2013)

  27. 27.

    et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491, 406–412 (2012)

  28. 28.

    et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT–PCR and expression vector cloning. J. Immunol. Methods 329, 112–124 (2008)

  29. 29.

    , , , & Sequences of Proteins of Immunological Interest (U.S. Department of Health and Human Services, National Institutes of Health, 1991)

  30. 30.

    & Selective recognition of oligomeric HIV-1 primary isolate envelope glycoproteins by potently neutralizing ligands requires efficient precursor cleavage. Virology 332, 145–156 (2005)

  31. 31.

    , , & HIV-1 virus-like particles bearing pure env trimers expose neutralizing epitopes but occlude nonneutralizing epitopes. J. Virol. 86, 3574–3587 (2012)

  32. 32.

    et al. Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer. Science 342, 1484–1490 (2013)

  33. 33.

    et al. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science 342, 1477–1483 (2013)

  34. 34.

    et al. A short segment of the HIV-1 gp120 V1/V2 region is a major determinant of resistance to V1/V2 neutralizing antibodies. J. Virol. 86, 8319–8323 (2012)

  35. 35.

    et al. High-throughput sequencing of the paired human immunoglobulin heavy and light chain repertoire. Nature Biotechnol. 31, 166–169 (2013)

  36. 36.

    et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N. Engl. J. Med. 366, 1275–1286 (2012)

  37. 37.

    et al. Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2. Nature 490, 417–420 (2012)

  38. 38.

    & The antibody response against HIV-1. Cold Spring Harb. Perspect. Med. 2, a007039 (2012)

  39. 39.

    , & Human peripheral blood antibodies with long HCDR3s are established primarily at original recombination using a limited subset of germline genes. PLoS ONE 7, e36750 (2012)

  40. 40.

    et al. IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains. Dev. Comp. Immunol. 27, 55–77 (2003)

  41. 41.

    et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003)

  42. 42.

    et al. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308, 1906–1908 (2005)

  43. 43.

    & Human antibodies that neutralize HIV-1: identification, structures, and B cell ontogenies. Immunity 37, 412–425 (2012)

  44. 44.

    et al. A blueprint for HIV vaccine discovery. Cell Host Microbe 12, 396–407 (2012)

  45. 45.

    et al. Isolation of human monoclonal antibodies from peripheral blood B cells. Nature Protocols 8, 1907–1915 (2013)

  46. 46.

    et al. Efficient protein boosting after plasmid DNA or recombinant adenovirus immunization with HIV-1 vaccine constructs. Vaccine 25, 1398–1408 (2007)

  47. 47.

    Measuring HIV neutralization in a luciferase reporter gene assay. Methods Mol. Biol. 485, 395–405 (2009)

  48. 48.

    et al. A rev1-vpu polymorphism unique to HIV-1 subtype A and C strains impairs envelope glycoprotein expression from rev-vpu-env cassettes and reduces virion infectivity in pseudotyping assays. Virology 397, 346–357 (2010)

  49. 49.

    et al. Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing. J. Virol. 82, 3952–3970 (2008)

  50. 50.

    , , , & Molecular architecture of native HIV-1 gp120 trimers. Nature 455, 109–113 (2008)

  51. 51.

    et al. Establishing a cohort at high risk of HIV infection in South Africa: challenges and experiences of the CAPRISA 002 acute infection study. PLoS ONE 3, e1954 (2008)

  52. 52.

    et al. High throughput HIV-1 microneutralization assay. Protocol Exchange (2013)

  53. 53.

    et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856–861 (2010)

  54. 54.

    et al. Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS Pathog. 9, e1003342 (2013)

  55. 55.

    et al. Automated molecular microscopy: the new Leginon system. J. Struct. Biol. 151, 41–60 (2005)

  56. 56.

    et al. Appion: an integrated, database-driven pipeline to facilitate EM image processing. J. Struct. Biol. 166, 95–102 (2009)

  57. 57.

    , , , & DoG Picker and TiltPicker: software tools to facilitate particle selection in single particle electron microscopy. J. Struct. Biol. 166, 205–213 (2009)

  58. 58.

    et al. A clustering approach to multireference alignment of single-particle projections in electron microscopy. J. Struct. Biol. 171, 197–206 (2010)

  59. 59.

    , , , & A new generation of the IMAGIC image processing system. J. Struct. Biol. 116, 17–24 (1996)

  60. 60.

    , & EMAN: semiautomated software for high-resolution single-particle reconstructions. J. Struct. Biol. 128, 82–97 (1999)

  61. 61.

    et al. Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948 (2007)

  62. 62.

    , , , & IMGT/HighV-QUEST: the IMGT web portal for immunoglobulin (IG) or antibody and T cell receptor (TR) analysis from NGS high throughput and deep sequencing. Immunome Res. 8, (2012)

  63. 63.

    , & Clustering of highly homologous sequences to reduce the size of large protein databases. Bioinformatics 17, 282–283 (2001)

  64. 64.

    , , , & Characterization of the human Ig heavy chain antigen binding complementarity determining region 3 using a newly developed software algorithm, JOINSOLVER. J. Immunol. 172, 6790–6802 (2004)

  65. 65.

    et al. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol. Biol. Evol. 28, 2731–2739 (2011)

  66. 66.

    & General time-reversible distances with unequal rates across sites: mixing gamma and inverse Gaussian distributions with invariant sites. Mol. Phylogenet. Evol. 8, 398–414 (1997)

  67. 67.

    et al. FastML: a web server for probabilistic reconstruction of ancestral sequences. Nucleic Acids Res. 40, W580–W584 (2012)

  68. 68.

    , , & WebLogo: a sequence logo generator. Genome Res. 14, 1188–1190 (2004)

  69. 69.

    & Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)

  70. 70.

    & Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)

  71. 71.

    et al. Recent developments in the PHENIX software for automated crystallographic structure determination. J. Synchrotron Radiat. 11, 53–55 (2004)

  72. 72.

    , , & MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes. Nucleic Acids Res. 32, W615–W619 (2004)

  73. 73.

    The PyMOL Molecular Graphics System. (DeLano Scientific, San Carlos, California, 2002)

  74. 74.

    et al. UCSF Chimera–a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004)

  75. 75.

    et al. Structural mechanism of trimeric HIV-1 envelope glycoprotein activation. PLoS Pathog. 8, e1002797 (2012)

  76. 76.

    et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329, 811–817 (2010)

  77. 77.

    et al. A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield. Science 334, 1097–1103 (2011)

  78. 78.

    , , , & Loop modeling: Sampling, filtering, and scoring. Proteins 70, 834–843 (2008)

  79. 79.

    , & FastTree 2–approximately maximum-likelihood trees for large alignments. PLoS ONE 5, e9490 (2010)

  80. 80.

    et al. Detecting individual sites subject to episodic diversifying selection. PLoS Genet. 8, e1002764 (2012)

  81. 81.

    , , & A maximum likelihood method for detecting directional evolution in protein sequences and its application to influenza A virus. Mol. Biol. Evol. 25, 1809–1824 (2008)

  82. 82.

    , & HyPhy: hypothesis testing using phylogenies. Bioinformatics 21, 676–679 (2005)

  83. 83.

    et al. The heterosexual human immunodeficiency virus type 1 epidemic in Thailand is caused by an intersubtype (A/E) recombinant of African origin. J. Virol. 70, 7013–7029 (1996)

Download references

Acknowledgements

We thank the participants in the CAPRISA 002 study for their commitment. For technical assistance and advice, we thank: K. Mlisana, S. Sibeko, N. Naicker, the CAPRISA 002 clinical team, N. Samsunder, S. Heeralall, B. Lambson, M. Madzivhandila, T. Khoza, C. Mitchell Scheepers, E. Turk, C.-L. Lin, M. Roederer, J. Stuckey, B. Hartman, G. Loots, J. H. Lee, G. Ippolito, B. Briney, S. Hunicke-Smith and J. Wheeler, and members of the WCMC HIVRAD Core and the NIH Vaccine Research Center HIMS, HIMC, SBS and SBIS sections. We thank J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra and L. Zhang for contributing the HIV-1 Envelope plasmids used in our neutralization panel. Funding was provided by the intramural research programs of the Vaccine Research Center and NIAID, the Fogarty International Center, NHGRI, and NIGMS of the National Institutes of Health, USA; the International AIDS Vaccine Initiative; the National Science Foundation; Scripps CHAV-ID; the South African Department of Science and Technology; and fellowships from the Wellcome Trust, Hertz Foundation, Donald D. Harrington Foundation, Poliomyelitis Research Foundation and the National Research Foundation of South Africa. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38.

Author information

Author notes

    • Nicole A. Doria-Rose
    • , Chaim A. Schramm
    • , Jason Gorman
    •  & Penny L. Moore

    These authors contributed equally to this work.

Affiliations

  1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Nicole A. Doria-Rose
    • , Jason Gorman
    • , Michael J. Ernandes
    • , Ivelin S. Georgiev
    • , Marie Pancera
    • , Ryan P. Staupe
    • , Han R. Altae-Tran
    • , Robert T. Bailer
    • , Aliaksandr Druz
    • , Rui Kong
    • , Mark K. Louder
    • , Nancy S. Longo
    • , Krisha McKee
    • , Sijy O’Dell
    • , Ryan S. Roark
    • , Rebecca S. Rudicell
    • , Stephen D. Schmidt
    • , Cinque Soto
    • , Yongping Yang
    • , Peter D. Kwong
    • , Lawrence Shapiro
    •  & John R. Mascola
  2. Department of Biochemistry, Columbia University, New York, New York 10032, USA

    • Chaim A. Schramm
    • , Zhenhai Zhang
    •  & Lawrence Shapiro
  3. Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa

    • Penny L. Moore
    • , Jinal N. Bhiman
    • , Molati Nonyane
    • , Constantinos Kurt Wibmer
    •  & Lynn Morris
  4. Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2050, South Africa

    • Penny L. Moore
    • , Jinal N. Bhiman
    • , Constantinos Kurt Wibmer
    •  & Lynn Morris
  5. Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Congella, 4013, South Africa

    • Penny L. Moore
    • , Nigel J. Garrett
    • , Carolyn Williamson
    • , Salim S. Abdool Karim
    •  & Lynn Morris
  6. Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, USA

    • Brandon J. DeKosky
    •  & George Georgiou
  7. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA

    • Helen J. Kim
    • , Ian A. Wilson
    •  & Andrew B. Ward
  8. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA

    • Helen J. Kim
    • , Ian A. Wilson
    •  & Andrew B. Ward
  9. IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA

    • Helen J. Kim
    • , Ian A. Wilson
    •  & Andrew B. Ward
  10. Torrey Pines Institute, San Diego, California 92037, USA

    • Ema T. Crooks
    •  & James M. Binley
  11. Weill Medical College of Cornell University, New York, New York 10065, USA

    • Albert Cupo
    •  & John P. Moore
  12. Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA

    • Kam H. Hoi
    •  & George Georgiou
  13. Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, University of Cape Town and NHLS, Cape Town 7701, South Africa

    • Daniel J. Sheward
    •  & Carolyn Williamson
  14. NISC Comparative Sequencing program, National Institutes of Health, Bethesda, Maryland 20892, USA

    • James C. Mullikin
  15. NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

    • James C. Mullikin
  16. Department of Medical Microbiology, Academic Medical Center, Amsterdam 1105 AZ, Netherlands

    • Rogier W. Sanders
  17. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA

    • Ian A. Wilson
  18. Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712, USA

    • George Georgiou
  19. Department of Epidemiology, Columbia University, New York, New York 10032, USA

    • Salim S. Abdool Karim

Consortia

  1. NISC Comparative Sequencing

    A list of authors and their affiliations appears in the Supplementary Information.

Authors

  1. Search for Nicole A. Doria-Rose in:

  2. Search for Chaim A. Schramm in:

  3. Search for Jason Gorman in:

  4. Search for Penny L. Moore in:

  5. Search for Jinal N. Bhiman in:

  6. Search for Brandon J. DeKosky in:

  7. Search for Michael J. Ernandes in:

  8. Search for Ivelin S. Georgiev in:

  9. Search for Helen J. Kim in:

  10. Search for Marie Pancera in:

  11. Search for Ryan P. Staupe in:

  12. Search for Han R. Altae-Tran in:

  13. Search for Robert T. Bailer in:

  14. Search for Ema T. Crooks in:

  15. Search for Albert Cupo in:

  16. Search for Aliaksandr Druz in:

  17. Search for Nigel J. Garrett in:

  18. Search for Kam H. Hoi in:

  19. Search for Rui Kong in:

  20. Search for Mark K. Louder in:

  21. Search for Nancy S. Longo in:

  22. Search for Krisha McKee in:

  23. Search for Molati Nonyane in:

  24. Search for Sijy O’Dell in:

  25. Search for Ryan S. Roark in:

  26. Search for Rebecca S. Rudicell in:

  27. Search for Stephen D. Schmidt in:

  28. Search for Daniel J. Sheward in:

  29. Search for Cinque Soto in:

  30. Search for Constantinos Kurt Wibmer in:

  31. Search for Yongping Yang in:

  32. Search for Zhenhai Zhang in:

  33. Search for James C. Mullikin in:

  34. Search for James M. Binley in:

  35. Search for Rogier W. Sanders in:

  36. Search for Ian A. Wilson in:

  37. Search for John P. Moore in:

  38. Search for Andrew B. Ward in:

  39. Search for George Georgiou in:

  40. Search for Carolyn Williamson in:

  41. Search for Salim S. Abdool Karim in:

  42. Search for Lynn Morris in:

  43. Search for Peter D. Kwong in:

  44. Search for Lawrence Shapiro in:

  45. Search for John R. Mascola in:

Contributions

N.A.D.-R., C.A.S., J.G. and P.L.M. contributed equally to this work. N.A.D.-R., C.A.S., J.G., P.L.M. and J.N.B., designed and performed experiments, analysed data and wrote the manuscript. L.M., P.D.K., L.S. and J.R.M. conceived and designed the experiments, analysed data, and wrote the manuscript. B.J.D., M.J.E., I.S.G, H.J.K., M.P. and R.P.S. conducted experiments and analysed data. H.R.A.-T., B.T.B., E.T.C., A.C., K.H.H., R.K., M.K.L., K.M., M.N., S.O., Ry.S.R., Re.S.R., S.D.S., C.K.W., Y.Y., J.C.M. and NISC conducted experiments. C.W. and A.D. contributed analysis tools and data analysis. S.S.A.K. and N.J.G conceived and managed the CAPRISA cohorts. J.M.B., R.W.S., I.A.W., J.P.M., A.B.W., G.G., N.S.L., D.J.S., C.S. and Z.Z. analysed data.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lynn Morris or Peter D. Kwong or Lawrence Shapiro or John R. Mascola.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary information

    This file contains Supplementary Notes, Supplementary Figures 1-11 and Supplementary Tables 1-5.

Text files

  1. 1.

    Supplementary Figure 12

    This file contains the NGS heavy chain reads in Nexus format.

  2. 2.

    Supplementary Figure 13

    This file contains the NGS light chain reads in Nexus format.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature13036

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.