Membrane embedded HIV-1 envelope on the surface of a virus-like particle elicits broader immune responses than soluble envelopes.
Virally regulated HIV-1 particles were expressed from DNA plasmids encoding Gag, protease, reverse transcriptase, Vpu, Tat, Rev, and Env. The sequences for integrase, Vpr, Vif, Nef, and the long terminal repeats (LTRs) were deleted. Mutations were engineered into the VLP genome to produce particles deficient in activities associated with viral reverse transcriptase, RNase H, and RNA packaging. Each plasmid efficiently secreted particles from primate cells in vitro and particles were purified from the supernatants and used as immunogens. Mice (BALB/c) were vaccinated intranasally (day 1 and weeks 3 and 6) with purified VLPs and the elicited immunity was compared to particles without Env (Gag(p55)), to soluble monomeric Env(gp120), or to soluble trimerized Env(gp140). Only mice vaccinated with VLPs had robust anti-Env cellular immunity. In contrast, all mice had high titer anti-Env serum antibody (IgG). However, VLP-vaccinated mice had antisera that detected a broader number of linear Env peptides, had anti-Env mucosal IgA and IgG, as well as higher titers of serum neutralizing antibodies. VLPs elicited high titer antibodies that recognized linear regions in V4-C5 and the ectodomain of gp41, but did not recognize V3. These lentiviral VLPs are effective mucosal immunogens that elicit broader immunity against Env determinants in both the systemic and mucosal immune compartments than soluble forms of Env.
McBurney
Sean P
SP
Center for Vaccine Research for Emerging Diseases and Biodefense, University of Pittsburgh School of Medicine, 9047 Biomedical Sciences Tower 3, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA.
Young
Kelly R
KR
Ross
Ted M
TM
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000281:Administration, Intranasal; D000818:Animals; D005260:Female; D015686:Gene Products, env / Q000276:immunology; D015483:HIV Antibodies / Q000032:analysis; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D007114:Immunization; D007115:Immunization Schedule; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D010957:Plasmids / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology*; D014771:Virion / Q000276:immunology*; D054299:env Gene Products, Human Immunodeficiency Virus
D016915:AIDS Vaccines; D015686:Gene Products, env; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D014614:Vaccines, Synthetic; D014759:Viral Envelope Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1