title: HIV-1 Envgp140 trimers elicit neutralizing antibodies without efficient induction of conformational antibodies.
abstract: Currently, no vaccine for human immunodeficiency virus (HIV-1) provides protection from virus infection. One reason for these disappointing results has been the difficulty of current vaccine candidates to elicit high-titer, broadly reactive immunity to a large number of viral proteins. Recently, our laboratory demonstrated that the coupling of C3d to a soluble trimerized HIV-1 envelope (Env(gp140(FT))) elicited higher titers of neutralizing antibodies than monomers of Env(gp120) coupled to C3d [Bower JF, Yang X, Sodroski J, Ross TM. Elicitation of neutralizing antibodies with DNA vaccines expressing soluble stabilized human immunodeficiency virus type 1 envelope glycoprotein trimers conjugated to C3d. J Virol 2004;78(9):4710-9]. To determine if the induction of conformational antibodies correlated with neutralization, mice (BALB/c) were primed (2x) with DNA plasmids expressing monomeric Env(gp120) or trimeric Env(gp140) alone or fused to mC3d(3) at one of two doses (2.0microg or 0.2microg), followed by a boost of recombinant uncleaved, trimeric Env(gp140). Regardless of the priming dose of DNA, all mice had high-titer anti-Env IgG antibodies. Interestingly, Env(gp140) trimers did not elicit higher titers of antibodies that recognized conformational Env epitopes compared to monomers of Env(gp120). Therefore, additional parameters were examined for correlation with neutralization. For neutralization-resistant HIV-1 isolates, ADA and YU-2, neutralization correlated with high-titer, high avidity antibodies, with Env(gp140) eliciting slightly higher neutralization titers than Env(gp120). In contrast, none of the measured parameters correlated with neutralization for the more neutralization-sensitive isolates, MN or 89.6. Therefore, even though soluble, uncleaved Env(gp140) trimers may be marginally more effective at eliciting neutralizing antibodies than Env(gp120), neutralization does not appear to correlate with the elicitation of conformationally dependent antibodies.
authors.affiliation: University of Pittsburgh, School of Medicine, Department of Medicine, Division of Infectious Diseases, Scaife Hall, Room S871, 3550 Terrace Street, Pittsburgh, PA 15261, USA. joseph.bower@sanofipasteur.com
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Bower
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.forename: Richard
authors.initials: R
authors.lastname: Wyatt
authors.forename: Ted M
authors.initials: TM
authors.lastname: Ross
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D000939:Epitopes; D015686:Gene Products, env / Q000276:immunology*; D015483:HIV Antibodies / Q000097:blood* / Q000737:chemistry; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA / Q000276:immunology*; D054299:env Gene Products, Human Immunodeficiency Virus
chemical_list: D016915:AIDS Vaccines; D000939:Epitopes; D015686:Gene Products, env; D015483:HIV Antibodies; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1