Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines1. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare2, information on the impact of the infecting virus strain on determining the breadth and specificity of the antibody responses to HIV-1 is lacking. Here we analyse the influence of viral antigens in shaping antibody responses in humans. We call the ability of a virus strain to induce similar antibody responses across different hosts its antibody-imprinting capacity, which from an evolutionary biology perspective corresponds to the viral heritability of the antibody responses. Analysis of 53 measured parameters of HIV-1-binding and neutralizing antibody responses in a cohort of 303 HIV-1 transmission pairs (individuals who harboured highly related HIV-1 strains and were putative direct transmission partners or members of an HIV-1 transmission chain) revealed that the effect of the infecting virus on the outcome of the bNAb response is moderate in magnitude but highly significant. We introduce the concept of bNAb-imprinting viruses and provide evidence for the existence of such viruses in a systematic screening of our cohort. The bNAb-imprinting capacity can be substantial, as indicated by a transmission pair with highly similar HIV-1 antibody responses and strong bNAb activity. Identification of viruses that have bNAb-imprinting capacities and their characterization may thus provide the potential to develop lead immunogens.
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The antibody response and patient data reported in this paper are completely tabulated in Supplementary Data 1, 2. Sequence data of T282–R282 Env consensus and Env clones reported in Fig. 2c are deposited in GenBank. Accession codes are listed in Extended Data Fig. 6b. The raw sequencing files of the Illumina full HIV sequencing data of patients T282 and R282 referred to in Fig. 2c and Extended Data Fig. 6 have been uploaded to https://zenodo.org/ (https://doi.org/10.5281/zenodo.1324259). pol sequence data of the 606 studied cases are available from the corresponding authors and/or the SHCS scientific board (http://www.shcs.ch/contact) upon request.
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Financial support for this study has been provided by the Swiss National Science Foundation (SNF; 314730_152663 and 314730_172790 to A.T.; 324730B_179571 to H.F.G.; PZ00P3-142411 and BSSGI0_155851 to R.D.K.), the Clinical Priority Research Program of the University of Zurich (Viral infectious diseases: Zurich Primary HIV Infection Study to H.F.G. and A.T.), the Yvonne-Jacob Foundation (to H.F.G.), the Swiss Vaccine Research Institute (to A.T., H.F.G. and R.D.K.) and the SystemsX.ch grant AntibodyX (to A.T.). This study has been cofinanced within the framework of the Swiss HIV Cohort Study, supported by the SNF (33CS30_148522 to H.F.G.), by the small nested SHCS project 744 (to A.T.) and by the SHCS research foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The SHCS data are collected by the five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers). We thank the patients participating in the ZPHI and the SHCS and their physicians and study nurses for patient care and D. Perraudin and M. Minichiello for administrative assistance.
Nature thanks P. Lemey, J. Overbaugh and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
About this article
Nature Reviews Microbiology (2018)