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

Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding.
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Kulp DW, Steichen JM, Pauthner M, Hu X, Schiffner T, Liguori A, Cottrell CA, Havenar-Daughton C, Ozorowski G, Georgeson E, Kalyuzhniy O, Willis JR, Kubitz M, Adachi Y, Reiss SM, Shin M, de Val N, Ward AB, Crotty S, Burton DR, Schief WR,


Kulp DW, Steichen JM, Pauthner M, Hu X, Schiffner T, Liguori A, Cottrell CA, Havenar-Daughton C, Ozorowski G, Georgeson E, Kalyuzhniy O, Willis JR, Kubitz M, Adachi Y, Reiss SM, Shin M, de Val N, Ward AB, Crotty S, Burton DR, Schief WR, (click to view)

Kulp DW, Steichen JM, Pauthner M, Hu X, Schiffner T, Liguori A, Cottrell CA, Havenar-Daughton C, Ozorowski G, Georgeson E, Kalyuzhniy O, Willis JR, Kubitz M, Adachi Y, Reiss SM, Shin M, de Val N, Ward AB, Crotty S, Burton DR, Schief WR,

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Nature communications 2017 11 218(1) 1655 doi 10.1038/s41467-017-01549-6

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.

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