title: Delivery of the HIV-1 Tat protein to dendritic cells by the CyaA vector induces specific Th1 responses and high affinity neutralizing antibodies in non human primates.
abstract: The human immunodeficiency virus type 1 (HIV-1) Tat is a key protein playing a major role in the infectivity of the virus. Thus, HIV-Tat based vaccines have been proposed as an attractive option to treat AIDS. Recently, we have shown that the recombinant detoxified adenylate cyclase (CyaA) from Bordetella pertussis carrying HIV-Tat (CyaA-E5-Tat), targets dendritic cells (DCs) and induces specific Th1 polarized and neutralizing antibody responses in mice. To further explore the potentialities of this prototype vaccine for human use, we analyzed the CyaA-E5-Tat induced antibody responses in non-human primates and established the biological characteristics of these antibodies. African Green Monkeys (AGM) were immunized with CyaA-E5-Tat in the presence or in the absence of alum adjuvant. First, we showed that the anti-CyaA antibodies induced by such immunization does not interfere with the binding of CyaA-E5-Tat to its receptor at the DC surface, the alphaMbeta2 integrin. Monkeys immunized with CyaA-E5-Tat, with or without alum, produced anti-Tat antibodies that mainly recognized the N-terminal domain of the Tat protein. Importantly, all sera obtained after three immunizations displayed the capacity to bind to Tat and neutralize its transactivating function in vitro. Finally, in the absence of alum, CyaA-E5-Tat, induced Th1 Tat specific T cell responses. These findings reveal that CyaA-E5-Tat is efficiently delivered in non-human primates and had a significant impact on the generation of neutralizing anti-Tat antibodies. These observations are, thus, encouraging for the use of the CyaA vector in human and also suggest that CyaA-E5-Tat might be a useful tool to decipher the biological characteristic of such antibodies.
authors.affiliation: Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, and INSERM E352, 75724 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mascarell
authors.forename: Cecile
authors.initials: C
authors.lastname: Bauche
authors.forename: Catherine
authors.initials: C
authors.lastname: Fayolle
authors.forename: Ousmane M
authors.initials: OM
authors.lastname: Diop
authors.forename: Monique
authors.initials: M
authors.lastname: Dupuy
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Nougarede
authors.forename: Ronald
authors.initials: R
authors.lastname: Perraut
authors.forename: Daniel
authors.initials: D
authors.lastname: Ladant
authors.forename: Claude
authors.initials: C
authors.lastname: Leclerc
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000262:Adenylyl Cyclases / Q000008:administration & dosage*; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D016764:Cell Polarity; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015696:Gene Products, tat / Q000276:immunology*; D015483:HIV Antibodies / Q000096:biosynthesis*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D018417:Th1 Cells / Q000276:immunology*; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D016915:AIDS Vaccines; D039481:CD11b Antigen; D015696:Gene Products, tat; D015483:HIV Antibodies; C421254:human immunodeficiency virus type 1 Tat vaccine; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma; D000262:Adenylyl Cyclases