Induction of neutralizing antibodies and Th1-polarized and CD4-independent CD8+ T-cell responses following delivery of human immunodeficiency virus type 1 Tat protein by recombinant adenylate cyclase of Bordetella pertussis.
HIV-Tat, a conserved protein playing a key role in the early life cycle of the human immunodeficiency virus (HIV) has been proposed as a potential AIDS vaccine. An HIV-Tat-based vaccine should elicit a broad, long-lasting, and neutralizing immune response. We have previously demonstrated that the adenylate cyclase (CyaA) from Bordetella pertussis targets dendritic cells and delivers CD8(+) and CD4(+) T-cell epitopes into the major histocompatibility complex class I and class II presentation pathways. We have also showed that CyaA induced specific and protective cytotoxic T cell responses in vivo. Here, we designed a prototype vaccine based on the HIV type 1 Tat delivered by CyaA (CyaA-E5-Tat) and tested its capacity to induce HIV-Tat-specific cellular as well as antibody responses. We showed that immunization of mice by CyaA-E5-Tat in the absence of adjuvant elicited strong and long-lasting neutralizing anti-Tat antibody responses more efficient than those obtained after immunization with Tat toxoid in aluminum hydroxide adjuvant. Analyses of the anti-Tat immunoglobulin G isotypes and the cytokine pattern showed that CyaA-E5-Tat induced a Th1-polarized immune response in contrast to the Th2-polarized immune responses obtained with the Tat toxoid. In addition, our data demonstrated that HIV-Tat-specific gamma interferon-producing CD8(+) T cells were generated after vaccination with CyaA-E5-Tat in a CD4(+) T-cell-independent manner. Based on these findings, CyaA-E5-Tat represents an attractive vaccine candidate for both preventive and therapeutic vaccination involving CyaA as an efficient nonreplicative vector for protein delivery.
Mascarell
Laurent
L
Unité de Biologie des Régulations Immunitaires, INSERM E 352, Institut Pasteur, Paris, France.
Fayolle
Catherine
C
Bauche
Cécile
C
Ladant
Daniel
D
Leclerc
Claude
C
D016915:AIDS Vaccines / Q000276:immunology*; D037361:Adenylate Cyclase Toxin / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004353:Drug Evaluation, Preclinical; D005260:Female; D015696:Gene Products, tat / Q000276:immunology*; D015483:HIV Antibodies / Q000097:blood*; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity; D018417:Th1 Cells / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus
D016915:AIDS Vaccines; D037361:Adenylate Cyclase Toxin; D015696:Gene Products, tat; D015483:HIV Antibodies; D011994:Recombinant Proteins; D014614:Vaccines, Synthetic; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma