title: Breadth of neutralizing antibodies elicited by stable, homogeneous clade A and clade C HIV-1 gp140 envelope trimers in guinea pigs.
abstract: The native envelope (Env) spike on the surface of human immunodeficiency virus type 1 (HIV-1) is trimeric, and thus trimeric Env vaccine immunogens are currently being explored in preclinical immunogenicity studies. Key challenges have included the production and purification of biochemically homogeneous and stable trimers and the evaluation of these immunogens utilizing standardized virus panels for neutralization assays. Here we report the binding and neutralizing antibody (NAb) responses elicited by clade A (92UG037.8) and clade C (CZA97.012) Env gp140 trimer immunogens in guinea pigs. These trimers have been selected and engineered for optimal biochemical stability and have defined antigenic properties. Purified gp140 trimers with Ribi adjuvant elicited potent, cross-clade NAb responses against tier 1 viruses as well as detectable but low-titer NAb responses against select tier 2 viruses from clades A, B, and C. In particular, the clade C trimer elicited NAbs that neutralized 27%, 20%, and 47% of tier 2 viruses from clades A, B, and C, respectively. Heterologous DNA prime, protein boost as well as DNA prime, recombinant adenovirus boost regimens expressing these antigens, however, did not result in an increased magnitude or breadth of NAb responses in this system. These data demonstrate the immunogenicity of stable, homogeneous clade A and clade C gp140 trimers and exemplify the utility of standardized tier 1 and tier 2 virus panels for assessing the NAb responses of candidate HIV-1 Env immunogens.
authors.affiliation: Division of Vaccine Research, Beth Israel Deaconess Medical Center, E/CLS-1047, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Nkolola
authors.forename: Hanqin
authors.initials: H
authors.lastname: Peng
authors.forename: Ethan C
authors.initials: EC
authors.lastname: Settembre
authors.forename: Michael
authors.initials: M
authors.lastname: Freeman
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Grandpre
authors.forename: Colleen
authors.initials: C
authors.lastname: Devoy
authors.forename: Diana M
authors.initials: DM
authors.lastname: Lynch
authors.forename: Annalena
authors.initials: A
authors.lastname: La Porte
authors.forename: Nathaniel L
authors.initials: NL
authors.lastname: Simmons
authors.forename: Ritu
authors.initials: R
authors.lastname: Bradley
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006168:Guinea Pigs; D015483:HIV Antibodies / Q000097:blood*; D007114:Immunization; D008969:Molecular Sequence Data; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1