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 ofBordetella pertussis

Abstract

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.

Pathogen Proteins Eliciting Antibodies Do Not Share Epitopes with Host Proteins: A Bioinformatics Approach

“…We made the same analysis for the rest of the pathogens in our study, which are Bordetella parapertussis, Bordetella pertussis, Chlamydia pneumoniae (Chlamydophila pneumoniae) and Mycoplasma pneumoniae . In the cases of Bordetella parapertussis and Bordetella pertussis, we were able to generate an ID of 28 and 37 sequences respectively [69]–[73]. For Chlamydia pneumoniae (Chlamydophila pneumoniae) , the ID was made up of 68 protein sequences [74]–[77].…”

Inclusion of the Bovine Neutrophil Beta-Defensin 3 with Glycoprotein D of Bovine Herpesvirus 1 in a DNA Vaccine Modulates Immune Responses of Mice and Cattle

“…Our data may be explained, however, by the findings of others. Reports have suggested that while Th1-type cyto- kines exert an overall negative effect on systemic humoral responses (79,81), they can have a positive effect on the magnitude of neutralizing antibody responses (82), and that neutralizing antibody responses can occur concurrent with induction of Th1-polarized responses (83)(84)(85). In particular, our results (VN antibody concurrent with induction of CTL) with this defensin-antigen fusion construct in cattle bears striking similarity to the results obtained when in the mouse model, an experimental DNA vaccine expressing murine beta-defensin 2 (mBD2) as a fusion with the gp120 antigen of HIV-1 induced systemic and mucosal CTLs and neutralizing antibody to the HIV-1 envelope protein in i.d.…”

Bordetella protein toxins

“…Up to now, adenylate cyclase toxoid harboring foreign antigens has already been proved to stimulate immunity against several viruses as LCMV [202][203][204][205][206], HIV [207], CMV [208], and influenza [209], as well as parasitic Plasmodium berghei [210,211], or to be a useful diagnostic tool for detecting latent tuberculosis [212] after the failure of induction of protective immunity against Mycobacterium tuberculosis [213]. Most important, CyaA-AC − was demonstrated to elicit both protective and therapeutic immune responses against HPV-16-induced tumors and melanoma in mice [214][215][216][217].…”