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Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape

Abstract

Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful1,2,3, a minority of individuals naturally develop these antibodies after many years of infection4,5,6,7. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.

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Figure 1: Characterizing the antibody specificities and viral populations in CAP177 and CAP314.
Figure 2: The glycan at position 332 mediates neutralization escape in CAP177 and CAP314.
Figure 3: The glycan at residue 332 is underrepresented in subtype C transmitted/founder viruses, which are also frequently resistant to the PGT128 mAb.

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Acknowledgements

We thank the participants in the CAPRISA 002 and 004 cohorts and the clinical and laboratory staff at CAPRISA for managing the cohort and providing specimens. 293T cells were obtained from G. Shaw (University of Alabama, Birmingham). We are grateful to D. Burton and W. Koff of the International AIDS Vaccine Initiative for providing the PGT monoclonal antibodies and to S. Gnanakaran (Los Alamos National Laboratories, Los Alamos, New Mexico) for providing transmitted/founder and chronic subtype B sequences. We thank Z. Valley-Omar and N. Ndabambi for generating some envelope sequences. We are grateful to B. Hahn and J. Kim, who contributed transmitted/founder subtype C clones to the Vaccine Immune Monitoring Core Standard Virus Panel Consortium. This work was funded by CAPRISA, the Centre for HIV/AIDS Vaccine Immunology, the South African HIV/AIDS Research and Innovation Platform of the South African Department of Science and Technology and by a US National Institutes of Health grant (number AI088610). CAPRISA was initially supported by the US National Institute of Allergy and Infectious Diseases, US National Institutes of Health, US Department of Health and Human Services grant U19 AI51794. M.S.S. is funded by the Bill & Melinda Gates Foundation, Vaccine Immune Monitoring Consortium of the Collaboration for AIDS Vaccine Discovery (grant 1032144). P.L.M. and E.S.G. were supported by the Columbia University-Southern African Fogarty AIDS International Training and Research Program through the Fogarty International Center, National Institutes of Health (grant 5 D43 TW000231). P.L.M. is a Wellcome Trust Intermediate Fellow in Public Health and Tropical Medicine (grant 089933/Z/09/Z).

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P.L.M. and E.S.G. designed the study, performed experiments, analyzed data and wrote the manuscript; E.S.G., C.K.W., J.N.B., T.H. and N.L.T. performed neutralization experiments and analyzed data; E.S.G., C.K.W., D.J.S., M.N., B.E.L. and N.R. generated single-genome sequences; D.J.S. and N.N. performed part of the sequence analyses; M.-R.A., L.P., R.I.S. and C.W. contributed the subtype C acute and chronic sequences; S.B. and M.S.S. designed and performed the neutralization experiments using the panel of transmitted/founder viruses; S.S.A.K., Q.A.K. and C.W. established the CAPRISA cohorts and contributed samples and data for these subjects; and L.M. designed the study and wrote the manuscript.

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Correspondence to Lynn Morris.

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Moore, P., Gray, E., Wibmer, C. et al. Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape. Nat Med 18, 1688–1692 (2012). https://doi.org/10.1038/nm.2985

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