DNA vaccines expressing soluble CD4-envelope proteins fused to C3d elicit cross-reactive neutralizing antibodies to HIV-1.
DNA vaccines expressing the envelope (Env) of the human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting, neutralizing antibodies in a variety of animal models. In this study, DNA vaccines were constructed to express a fusion protein of the soluble human CD4 (sCD4) and the gp120 subunit of the HIV-1 envelope. To enhance the immunogenicity of the expressed fusion protein, three copies of the murine C3d (mC3d3) were added to the carboxyl terminus of the complex. Monoclonal antibodies that recognize CD4-induced epitopes on gp120 efficiently bound to sCD4-gp120 or sCD4-gp120-mC3d3. In addition, both sCD4-gp120 and sCD4-gp120-mC3d3 bound to cells expressing appropriate coreceptors in the absence of cell surface hCD4. Mice (BALB/c) vaccinated with DNA vaccines expressing either gp120-mC3d3 or sCD4-gp120-mC3d3 elicited antibodies that neutralized homologous virus infection. However, the use of sCD4-gp120-mC3d3-DNA elicited the highest titers of neutralizing antibodies that persisted after depletion of anti-hCD4 antibodies. Interestingly, only mice vaccinated with DNA expressing sCD4-gp120-mC3d3 had antibodies that elicited cross-protective neutralizing antibodies. The fusion of sCD4 to the HIV-1 envelope exposes neutralizing epitopes that elicit broad protective immunity when the fusion complex is coupled with the molecular adjuvant, C3d.
Department of Medicine, Division of Infectious Diseases, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA.
Joseph F
JF
Bower
Thomas D
TD
Green
Ted M
TM
Ross
D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D015933:Complement C3d / Q000276:immunology*; D015483:HIV Antibodies / Q000096:biosynthesis / Q000097:blood*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D007114:Immunization; D007271:Injections, Intradermal; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology*
D016915:AIDS Vaccines; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D019444:Vaccines, DNA; C076613:recombinant soluble CD4; D015933:Complement C3d