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.
Bower
Joseph F
JF
Department of Medicine, Division of Infectious Diseases, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA.
Green
Thomas D
TD
Ross
Ted M
TM
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