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Aberrant B cell repertoire selection associated with HIV neutralizing antibody breadth

Nature Immunology volume 21, pages 199–209 (2020)Cite this article

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Abstract

A goal of HIV vaccine development is to elicit antibodies with neutralizing breadth. Broadly neutralizing antibodies (bNAbs) to HIV often have unusual sequences with long heavy-chain complementarity-determining region loops, high somatic mutation rates and polyreactivity. A subset of HIV-infected individuals develops such antibodies, but it is unclear whether this reflects systematic differences in their antibody repertoires or is a consequence of rare stochastic events involving individual clones. We sequenced antibody heavy-chain repertoires in a large cohort of HIV-infected individuals with bNAb responses or no neutralization breadth and uninfected controls, identifying consistent features of bNAb repertoires, encompassing thousands of B cell clones per individual, with correlated T cell phenotypes. These repertoire features were not observed during chronic cytomegalovirus infection in an independent cohort. Our data indicate that the development of numerous B cell lineages with antibody features associated with autoreactivity may be a key aspect in the development of HIV neutralizing antibody breadth.

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Fig. 1: Differences in SHM frequency in antibody heavy-chain transcripts in HIV-uninfected controls and HIV-infected bNAb and noNAb individuals.
Fig. 2: Differences in the length of the CDR-H3 of antibody heavy chains in healthy controls compared to HIV-infected bNAb and noNAb individuals.
Fig. 3: Average heavy-chain CDR-H3 lengths in IGH repertoire fractions with increasing frequencies of SHM.
Fig. 4: Correlation of Ig heavy-chain features and T cell subsets.
Fig. 5: IGHV segment usage and SHM analysis of clones using IGHV4-34.
Fig. 6: Clonality analysis.
Fig. 7: Prediction of HIV and bNAb status.

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Data availability

The B cell heavy-chain sequences analyzed here are available through the Short Read Archive. Data from the HIV cohort can be found in the BioProject PRJNA486667. Data from CMV-seropositive and seronegative healthy controls are deposited as BioProject PRJNA491287.

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Acknowledgements

We gratefully acknowledge the participants who volunteered for this study. Support for this work was provided by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS; UM-1 grant for the Duke Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery AI100645; National Institutes of Health grant Nos. R21-AI100696, CHAVI-AI0678501, R01AI127877 and R01AI130398; and MRC Programme grant No. MR/ K012037.

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Authors and Affiliations

  1. Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, USA

    Krishna M. Roskin

  2. Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Krishna M. Roskin

  3. Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Krishna M. Roskin

  4. Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    Katherine J. L. Jackson

  5. Department of Pathology, Stanford University, Stanford, CA, USA

    Ji-Yeun Lee, Ramona A. Hoh, Shilpa A. Joshi, Andrew Z. Fire & Scott D. Boyd

  6. Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA

    Kwan-Ki Hwang, Mattia Bonsignori, Hua-Xin Liao, M. Anthony Moody & Barton F. Haynes

  7. Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

    Isabela Pedroza-Pacheco & Persephone Borrow

  8. Department of Genetics, Stanford University, Stanford, CA, USA

    Andrew Z. Fire

  9. Department of Medicine, Duke University School of Medicine, Durham, NC, USA

    Barton F. Haynes

  10. Department of Immunology, Duke University School of Medicine, Durham, NC, USA

    Barton F. Haynes

  11. Duke Global Health Institute, Duke University School of Medicine, Durham, NC, USA

    Barton F. Haynes

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Contributions

K.M.R., A.Z.F., P.B., B.F.H. and S.D.B. conceptualized the study. K.M.R., K.J.L.J., I.P.-P., B.F.H. and S.D.B. were responsible for the methodology. K.M.R. and K.J.L.J. were responsible for the software. K.M.R., J.-Y.L., R.A.H., I.P.-P., K.-K.H., H.-X.L. and S.A.J. managed the investigation. K.M.R., K.J.L.J., S.D.B., I.P.-P., P.B., M.A.M., M.B. and K.-K.H. handled the formal analysis. K.-K.H., M.B., H.-X.L., M.A.M., P.B., B.F.H. and S.D.B. collected the resources. K.M.R. curated the data. K.M.R. and S.D.B. wrote the original draft of the manuscript. K.M.R., K.J.L.J., B.F.H., M.B., M.A.M., P.B., S.A.J. and S.D.B. reviewed and edited the manuscript. K.M.R. was responsible for the visualization. P.B., B.F.H. and S.D.B. supervised the project. P.B., B.F.H. and S.D.B. were responsible for funding acquisition.

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Correspondence to Barton F. Haynes or Scott D. Boyd.

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Competing interests

A patent application related to computational methods used in this paper is in preparation by K.M.R. and S.D.B.

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Peer review information L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Roskin, K.M., Jackson, K.J.L., Lee, JY. et al. Aberrant B cell repertoire selection associated with HIV neutralizing antibody breadth. Nat Immunol 21, 199–209 (2020). https://doi.org/10.1038/s41590-019-0581-0

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