Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding

Daniel W. Kulp, Jon M. Steichen, Matthias Pauthner, Xiaozhen Hu, Torben Schiffner, Alessia Liguori, Christopher A. Cottrell, Colin Havenar-Daughton, Gabriel Ozorowski, Erik Georgeson, Oleksandr Kalyuzhniy, Jordan R. Willis, Michael Kubitz, Yumiko Adachi, Samantha M. Reiss, Mia Shin, Natalia Val, Andrew B. Ward, Shane Crotty, Dennis R. Burton and William R. Schief ()
Additional contact information
Daniel W. Kulp: The Scripps Research Institute
Jon M. Steichen: The Scripps Research Institute
Matthias Pauthner: The Scripps Research Institute
Xiaozhen Hu: The Scripps Research Institute
Torben Schiffner: The Scripps Research Institute
Alessia Liguori: The Scripps Research Institute
Christopher A. Cottrell: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Colin Havenar-Daughton: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
Gabriel Ozorowski: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Erik Georgeson: The Scripps Research Institute
Oleksandr Kalyuzhniy: The Scripps Research Institute
Jordan R. Willis: The Scripps Research Institute
Michael Kubitz: The Scripps Research Institute
Yumiko Adachi: The Scripps Research Institute
Samantha M. Reiss: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
Mia Shin: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Natalia Val: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Andrew B. Ward: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Shane Crotty: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
Dennis R. Burton: The Scripps Research Institute
William R. Schief: The Scripps Research Institute

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Elicitation of broadly neutralizing antibodies (bnAbs) is a primary HIV vaccine goal. Native-like trimers mimicking virion-associated spikes present nearly all bnAb epitopes and are therefore promising vaccine antigens. However, first generation native-like trimers expose epitopes for non-neutralizing antibodies (non-nAbs), which may hinder bnAb induction. We here employ computational and structure-guided design to develop improved native-like trimers that reduce exposure of non-nAb epitopes in the V3-loop and trimer base, minimize both CD4 reactivity and CD4-induced non-nAb epitope exposure, and increase thermal stability while maintaining bnAb antigenicity. In rabbit immunizations with native-like trimers of the 327c isolate, improved trimers suppress elicitation of V3-directed and tier-1 neutralizing antibodies and induce robust autologous tier-2 neutralization, unlike a first-generation trimer. The improved native-like trimers from diverse HIV isolates, and the design methods, have promise to assist in the development of a HIV vaccine.

Date: 2017
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DOI: 10.1038/s41467-017-01549-6

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