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

Nat Commun. 2017 Nov 21;8(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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AIDS Vaccines / administration & dosage
  • AIDS Vaccines / chemistry*
  • AIDS Vaccines / genetics
  • AIDS Vaccines / immunology*
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology*
  • CD4 Antigens / genetics
  • CD4 Antigens / immunology*
  • Epitopes / chemistry
  • Epitopes / genetics
  • Epitopes / immunology
  • Female
  • HIV Infections / immunology
  • HIV Infections / virology*
  • HIV-1 / chemistry
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • Humans
  • Immunization
  • Protein Multimerization
  • Rabbits
  • env Gene Products, Human Immunodeficiency Virus / administration & dosage
  • env Gene Products, Human Immunodeficiency Virus / chemistry*
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • CD4 Antigens
  • Epitopes
  • env Gene Products, Human Immunodeficiency Virus