Determinants of HIV-1 broadly neutralizing antibody induction

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Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen—viral load, length of untreated infection and viral diversity—independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086–0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non–subtype B viruses (P = 1 × 10−5). Thus, key host, disease and viral determinants, including subtype-specific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design.

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Figure 1: Primary 8-virus neutralization screen identifies 239 bnAb-inducing individuals.
Figure 2: Primary 8-virus screen detects broad and potent neutralization.
Figure 3: Influence of viral and disease parameters on the development of neutralization breadth.
Figure 4: Ethnicity influences the development of neutralization breadth.
Figure 5: Influence of HIV-1 subtype on the type of bnAb response.


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We thank the patients participating in the ZPHI and the SHCS and their physicians and study nurses for patient care; B. Remy, F. Schoeni-Affolter and Y. Vallet from the SHCS Data Center in Lausanne for data management; M. Robbiani, D. Perraudin and M. Minichiello for administrative assistance. We thank D. Burton (the Scripps Research Institute), J. Mascola (US National Institutes of Health (NIH) Vaccine Research Center), M. Nussenzweig (Rockefeller University), M. Connors (NIH), D. Katinger (Polymun), P. Moore and L. Morris (Center for Communicable Diseases, South Africa) for providing antibodies and/or antibody expression plasmids for this study, either directly or via the NIH AIDS Research and Reference Reagent Program. Financial support for this study was provided by the Swiss National Science Foundation (grant 310030_152663 to A.T.), the Clinical Priority Research Priority 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., R.D.K., R.R.R. and J.F.) and a grant (AntibodyX to A.T. and R.R.R.). R.D.K. was supported by the Swiss National Science Foundation (PZ00P3-142411 and BSSGI0_155851). This study was cofunded within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant 33CS30_148522 to H.F.G.), the small nested SHCS project 744 (to A.T.) and the SHCS research foundation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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P.R., R.D.K., H.F.G. and A.T. conceived and designed the study and analyzed data. P.R., H.E., M.S., M. Huber, C.W.T. and J.F. designed and performed experiments and analyzed data. J.W., T.U., V.C., H.K., S.Y., V.A., T.K. and J.B. conducted experiments and analyzed data. C.K., A.S., C.M., N.H. and R.R.R. conducted computational analyses and contributed analysis tools and data analysis. D.L.B., M.C., E.B., M. Hoffmann, A.C., M.B., A.R., H.F.G. and the members of the Swiss HIV Cohort Study conceived and managed the SHCS and ZPHI cohorts collected and contributed patient samples and clinical data. P.R., R.D.K., M.S., C.K., M. Huber, H.F.G. and A.T. wrote the manuscript, which all coauthors commented on.

Correspondence to Huldrych F Günthard or Alexandra Trkola.

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Rusert, P., Kouyos, R., Kadelka, C. et al. Determinants of HIV-1 broadly neutralizing antibody induction. Nat Med 22, 1260–1267 (2016) doi:10.1038/nm.4187

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