Abstract

The elicitation of broadly neutralizing antibodies (bNAbs) is likely to be essential for a preventative HIV-1 vaccine, but this has not yet been achieved by immunization. In contrast, some HIV-1-infected individuals naturally mount bNAb responses during chronic infection, suggesting that years of maturation may be required for neutralization breadth1,2,3,4,5,6. Recent studies have shown that viral diversification precedes the emergence of bNAbs, but the significance of this observation is unknown7,8. Here we delineate the key viral events that drove neutralization breadth within the CAP256-VRC26 family of 33 monoclonal antibodies (mAbs) isolated from a superinfected individual. First, we identified minority viral variants, termed bNAb-initiating envelopes, that were distinct from both of the transmitted/founder (T/F) viruses and that efficiently engaged the bNAb precursor. Second, deep sequencing revealed a pool of diverse epitope variants (immunotypes) that were preferentially neutralized by broader members of the antibody lineage. In contrast, a 'dead-end' antibody sublineage unable to neutralize these immunotypes showed limited evolution and failed to develop breadth. Thus, early viral escape at key antibody-virus contact sites selects for antibody sublineages that can tolerate these changes, thereby providing a mechanism for the generation of neutralization breadth within a developing antibody lineage.

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Acknowledgements

We thank the participants in the CAPRISA 002 cohort for their commitment to attending the CAPRISA clinics in South Africa. Thanks to the CAPRISA 002 study team (including N. Naicker, V. Asari, N. Majola, T. Cekwane, N. Samsunder, Z. Mchunu, D. Nkosi, H. Shozi, S. Ndlovu, P. Radebe, K. Leask and M. Upfold) for managing the cohort and providing specimens. We are grateful to C. K. Wibmer for useful discussions. We thank P. Labuschagne, D. Matten and T. York for assistance with viral next-generation sequence analysis, R. Bailer and M. Louder for the CAP256-VRC26 UCA neutralization data against the large virus panel and J. Mulllikin and the US National Institutes of Health (NIH) Intramural Sequencing Center (NISC) Comparative Sequencing Program for antibody NGS data at 34 weeks. We are grateful to 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. The JC53bl-13 (TZM-bl) and 293T cell lines were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH from J.C. Kappes, X. Wu and Tranzyme, Inc., and A. Rice, respectively. We acknowledge research funding from the Centre for the AIDS Programme of Research (CAPRISA) (S.S.A.K.), the South African Medical Research Council (MRC) SHIP program (P.L.M.), the NIH through a U01 grant (AI116086-01) (P.L.M.), the intramural research programs of the Vaccine Research Center and the National Institute of Allergy and Infectious Diseases (NIAID) (J.R.M.). CAPRISA is funded by the South African HIV/AIDS Research and Innovation Platform of the South African Department of Science and Technology, and was initially supported by the US NIAID, NIH, US Department of Health and Human Services grant U19 AI51794 (S.S.A.K.). Funding was received by J.N.B. and C.A. from the Columbia University-Southern African Fogarty AIDS International Training and Research Program through the Fogarty International Center, NIH grant 5 D43 TW000231 (to Quarraisha Abdool Karim). Additional fellowships included a University of the Witwatersrand Postgraduate Merit Award (J.N.B.), a Poliomyelitis Research Foundation PhD Bursary (J.N.B.), a National Research Foundation of South Africa Innovation PhD Bursary (J.N.B.), a National Research Foundation of South Africa Postdoctoral Fellowship (C.A.), and a Wellcome Trust Intermediate Fellowship in Public Health and Tropical Medicine, grant 089933/Z/09/Z (P.L.M.).

Author information

Affiliations

  1. Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa.

    • Jinal N Bhiman
    • , Owen Karimanzira
    • , Thandeka Khoza
    • , Dale Kitchin
    • , Lynn Morris
    •  & Penny L Moore
  2. Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

    • Jinal N Bhiman
    • , Lynn Morris
    •  & Penny L Moore
  3. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.

    • Colin Anthony
    • , Gordon Botha
    •  & Carolyn Williamson
  4. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Nicole A Doria-Rose
    • , Jason Gorman
    • , Lawrence Shapiro
    • , Peter D Kwong
    •  & John R Mascola
  5. Department of Biochemistry and Systems Biology, Columbia University, New York, New York, USA.

    • Chaim A Schramm
    •  & Lawrence Shapiro
  6. Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban, South Africa.

    • Nigel J Garrett
    • , Salim S Abdool Karim
    • , Carolyn Williamson
    • , Lynn Morris
    •  & Penny L Moore
  7. National Health Laboratory Services, Johannesburg, South Africa.

    • Carolyn Williamson

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Contributions

J.N.B., L.M. and P.L.M. designed the study, analyzed data and wrote the manuscript. C.A. and C.W. designed and performed viral NGS and analysis and edited the manuscript. N.A.D.-R. led the isolation of CAP256 mAbs. J.N.B. and O.K. performed neutralization experiments. C.A.S. and L.S. generated and analyzed antibody NGS data. J.N.B. and T.K. expressed and purified monoclonal antibodies. J.N.B. and D.K. generated single-genome sequences and viral envelope clones. G.B. developed computational tools to analyze NGS data, and assisted in the NGS analysis. J.G. assessed CAP256-VRC26 UCA neutralization of heterologous viruses. N.J.G. and the CAPRISA Study Team managed the CAPRISA cohort and contributed samples and data for CAP256. S.S.A.K., C.W. and L.M. established and led the CAPRISA cohort. C.W., N.A.D.-R., L.S., P.D.K., and J.R.M. contributed to data analysis and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Penny L Moore.

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https://doi.org/10.1038/nm.3963

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