title: Biochemical and immunogenic characterization of soluble human immunodeficiency virus type 1 envelope glycoprotein trimers expressed by semliki forest virus.
abstract: The current lack of envelope glycoprotein immunogens that elicit broadly neutralizing antibody responses remains a major challenge for human immunodeficiency virus type 1 (HIV-1) vaccine development. However, the recent design and construction of stable soluble gp140 trimers have shown that some neutralization breadth can be achieved by using immunogens that better mimic the functional viral spike complex. The use of genetic delivery systems to drive the in vivo expression of such immunogens for the stimulation of neutralizing antibodies against HIV-1 may offer advantages by maintaining the quaternary structure of the trimeric envelope glycoproteins. Here, we describe the biochemical and immunogenic properties of soluble HIV-1 envelope glycoprotein trimers expressed by recombinant Semliki Forest virus (rSFV). The results presented here demonstrate that rSFV supports the expression of stable soluble gp140 trimers that retain recognition by conformationally sensitive antibodies. Further, we show that rSFV particle immunizations efficiently primed immune responses as measured after a single boost with purified trimeric gp140 protein, resulting in a Th1-biased antibody response. This differed from the Th2-biased antibody response obtained after repeated immunizations with purified gp140 protein trimers. Despite this difference, both regimens stimulated neutralizing antibody responses of similar potency. This suggests that rSFV may be a useful component of a viral vector prime-protein boost regimen aimed at stimulating both cell-mediated immune responses and neutralizing antibodies against HIV-1.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mattias N E
authors.initials: MN
authors.lastname: Forsell
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.forename: Maria
authors.initials: M
authors.lastname: Sundbäck
authors.forename: Krisha
authors.initials: K
authors.lastname: Svehla
authors.forename: Peter
authors.initials: P
authors.lastname: Liljeström
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Richard
authors.initials: R
authors.lastname: Wyatt
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
mesh_terms: D016915:AIDS Vaccines / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D015686:Gene Products, env / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D015483:HIV Antibodies / Q000097:blood; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D007114:Immunization; D007115:Immunization Schedule; D018655:Lymphocyte Count; D051379:Mice; D009500:Neutralization Tests; D011817:Rabbits; D012672:Semliki forest virus / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology / Q000378:metabolism; D054299:env Gene Products, Human Immunodeficiency Virus
chemical_list: D016915:AIDS Vaccines; D015686:Gene Products, env; D015483:HIV Antibodies; D014614:Vaccines, Synthetic; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1