Kulp, Daniel W.Steichen, Jon M.Pauthner, MatthiasHu, XiaozhenSchiffner, TorbenLiguori, AlessiaCottrell, Christopher A.Havenar-Daughton, ColinOzorowski, GabrielGeorgeson, ErikKalyuzhniy, OleksandrWillis, Jordan R.Kubitz, MichaelAdachi, YumikoReiss, Samantha M.Shin, Miade Val, NataliaWard, Andrew B.Crotty, ShaneBurton, Dennis R.Schief, William R.2017-12-062017Kulp, D. W., J. M. Steichen, M. Pauthner, X. Hu, T. Schiffner, A. Liguori, C. A. Cottrell, et al. 2017. “Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding.” Nature Communications 8 (1): 1655. doi:10.1038/s41467-017-01549-6. http://dx.doi.org/10.1038/s41467-017-01549-6.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493196Elicitation 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.en-USJournal Article2017-12-0610.1038/s41467-017-01549-6