title: Quaternary protein mimetics of gp41 elicit neutralizing antibodies against HIV fusion-active intermediate state.
abstract: During viral entry, the fusogenic state of human immunodeficiency virus Type 1 (HIV-1) envelope protein gp41 is a quaternary structure consisting of three gp41 glycoproteins, each with two conserved helical domains (N-HR and C-HR). Thus far, the examination of monomeric gp41 peptides as an immunologically focused approach to vaccine design has not been successful. Here we report an approach using quaternary protein mimetics (called 3alpha mimetics) that are based on the gp41 N-HR and C-HR domains to closely mimic the fusogenic state and overcome the deficiencies of the monomeric peptide approach for synthetic vaccine design. The 3alpha mimetics are conveniently prepared by chemoselective ligation of unprotected monomeric peptides to an interstrand linker, and display enhanced conformational stability compared to the corresponding monomers. The 3alpha mimetics with or without a covalently attached T-helper epitope were immunogenic and elicited antisera that bound both recombinant gp160, which contains gp41, and HIV-1 virions and immunoprecipitated recombinant gp41. Anti-3alpha mimetic antisera neutralized viral infectivity against R5- and X4-tropic strains of HIV-1 at 31.5 degrees C. The results suggest that a quaternary protein approach to mimic conserved and functional domains of viral envelope proteins is desirable for HIV vaccine development as such antigens are more likely to produce immunologically-focused and broadly neutralizing antibody responses.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore. kesadler@ntu.edu.sg
authors.forename: Kristen
authors.initials: K
authors.lastname: Sadler
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Xu
authors.forename: Qitao
authors.initials: Q
authors.lastname: Yu
authors.forename: James P
authors.initials: JP
authors.lastname: Tam
mesh_terms: D000818:Animals; D032701:Biomimetics; D002459:Cell Fusion / Q000379:methods; D005260:Female; D006168:Guinea Pigs; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology*; D019302:HIV Envelope Protein gp160 / Q000737:chemistry / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D009500:Neutralization Tests; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology; D014771:Virion / Q000737:chemistry
chemical_list: D015483:HIV Antibodies; D019302:HIV Envelope Protein gp160; D015700:HIV Envelope Protein gp41; D011994:Recombinant Proteins