title: Ancestral and consensus envelope immunogens for HIV-1 subtype C.
abstract: Immunogens based on "centralized" (ancestral or consensus) HIV-1 sequences minimize the genetic distance between vaccine strains and contemporary viruses and should thus elicit immune responses that recognize a broader spectrum of viral variants. However, the biologic, antigenic and immunogenic properties of such inferred gene products have to be validated experimentally. Here, we report the construction and characterization of the first full-length ancestral (AncC) and consensus (ConC) env genes of HIV-1 (group M) subtype C. The codon-usage-optimized genes expressed high levels of envelope glycoproteins that were incorporated into HIV-1 virions, mediated infection via the CCR5 co-receptor and retained neutralizing epitopes as recognized by plasma from patients with chronic HIV-1 subtype C infection. Guinea pigs immunized with AncC and ConC env DNA developed high titer binding, but no appreciable homologous or heterologous neutralizing antibodies. When tested by immunoblot analysis, sera from AncC and ConC env immunized guinea pigs recognized a greater number of primary subtype C envelope glycoproteins than sera from guinea pigs immunized with a contemporary subtype C env control. Mice immunized with AncC and ConC env DNA developed gamma interferon T cell responses that recognized overlapping peptides from the cognate ConC and a heterologous subtype C Env control. Thus, both AncC and ConC env genes expressed functional envelope glycoproteins that were immunogenic in laboratory animals and elicited humoral and cellular immune responses of comparable breadth and magnitude. These results establish the utility of centralized HIV-1 subtype C Env immunogens and warrant their continued evaluation as potential components of future AIDS vaccines.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Denise L
authors.initials: DL
authors.lastname: Kothe
authors.forename: Yingying
authors.initials: Y
authors.lastname: Li
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Zammit
authors.forename: Maria G
authors.initials: MG
authors.lastname: Salazar
authors.forename: Yalu
authors.initials: Y
authors.lastname: Chen
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.forename: Eric A
authors.initials: EA
authors.lastname: Weaver
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Bette T M
authors.initials: BT
authors.lastname: Korber
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D016384:Consensus Sequence; D003429:Cross Reactions; D019143:Evolution, Molecular; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology; D015752:Genes, env; D006168:Guinea Pigs; D015483:HIV Antibodies / Q000097:blood; D015488:HIV Antigens / Q000235:genetics; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000145:classification* / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid
chemical_list: D016915:AIDS Vaccines; D015686:Gene Products, env; D015483:HIV Antibodies; D015488:HIV Antigens