|Title||Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||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|
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.
|Alternate Journal||Nat Commun|
|PubMed Central ID||PMC5698488|
|Grant List||UM1 AI100663 / AI / NIAID NIH HHS / United States|
Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding.