title: Human immunodeficiency virus type 1 env trimer immunization of macaques and impact of priming with viral vector or stabilized core protein.
abstract: Currently there is limited information about the quality of immune responses elicited by candidate human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env)-based immunogens in primates. Here we describe a comprehensive analysis of neutralizing antibody and T-cell responses obtained in cynomolgus macaques by three selected immunization regimens. We used the previously described YU2-based gp140 protein trimers administered in an adjuvant, preceded by two distinct priming strategies: either alphavirus replicon particles expressing matched gp140 trimers or gp120 core proteins stabilized in the CD4-bound conformation. The rationale for priming with replicon particles was to evaluate the impact of the expression platform on trimer immunogenicity. The stable core proteins were chosen in an attempt to expand selectively lymphocytes recognizing common determinants between the core and trimers to broaden the immune response. The results presented here demonstrate that the platform by which Env trimers were delivered in the priming (either protein or replicon vector) had little impact on the overall immune response. In contrast, priming with stable core proteins followed by a trimer boost strikingly focused the T-cell response on the core sequences of HIV-1 Env. The specificity of the T-cell response was distinctly different from that of the responses obtained in animals immunized with trimers alone and was shown to be mediated by CD4(+) T cells. However, this regimen showed limited or no improvement in the neutralizing antibody responses, suggesting that further immunogen design efforts are required to successfully focus the B-cell response on conserved neutralizing determinants of HIV-1 Env.
authors.affiliation: Swedish Institute for Infectious Disease Control, Solna, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mörner
authors.forename: Iyadh
authors.initials: I
authors.lastname: Douagi
authors.forename: Mattias N E
authors.initials: MN
authors.lastname: Forsell
authors.forename: Christopher
authors.initials: C
authors.lastname: Sundling
authors.forename: Pia
authors.initials: P
authors.lastname: Dosenovic
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.forename: Barna
authors.initials: B
authors.lastname: Dey
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Gerald
authors.initials: G
authors.lastname: Voss
authors.forename: Rigmor
authors.initials: R
authors.lastname: Thorstensson
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000524:Alphavirus / Q000235:genetics; D000818:Animals; D005822:Genetic Vectors; D015483:HIV Antibodies / Q000097:blood; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods*; D008252:Macaca fascicularis; D009500:Neutralization Tests; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination / Q000379:methods*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus