title: HIV-1 Tat protein vaccination in mice infected with Mycobacterium tuberculosis is safe, immunogenic and reduces bacterial lung pathology.
abstract: The therapeutic HIV-1 Tat protein vaccine is in advanced clinical development. Tuberculosis, the main AIDS co-infection, is highly endemic in areas where AIDS prevention through vaccination is needed. However, safety and immunogenicity of Tat vaccination in the course of Mycobacterium tuberculosis (Mtb) infection is still unknown and it prevents the possibility to administer the vaccine to Mtb-infected individuals. We addressed the interplay and effects of Tat vaccination on Mtb infection in immunocompetent mice.
  
  
  
  C57BL/6 mice were vaccinated or not with Bacillus Calmette-Guerin (BCG), the current tuberculosis vaccine, and after 5 weeks were infected with Mtb by intravenous route. The Tat protein was injected intradermally at 1, 2 and 4 weeks after Mtb challenge. Eight weeks after Mtb infection, all mice were sacrificed, and both the degree of pathology and immune responses to Mtb and Tat were evaluated. As additional control, some mice were either vaccinated or not with BCG, were not challenged with Mtb, but received the Tat protein. Statistical significances were evaluated by one-way or two-way ANOVA and Tukey's multiple comparisons post-test.
  
  
  
  In the lungs of Mtb-infected mice, Tat-vaccine did not favour Mtb replication and indeed reduced both area of cellular infiltration and protein levels of Interferon-γ, Chemokine (C-C motif) ligand-4 and Interleukin-1β, pathological events triggered by Mtb-infection. Moreover, the protection against Mtb infection conferred by BCG remained good after Tat protein treatment. In spleen cells of Mtb-infected mice, Tat vaccination enhanced Mtb-specific Interferon-γ and Interleukin-17 responses, which may have a protective role. Of note, Mtb infection reduced, but did not suppress, the development of anti-Tat antibodies, required for Tat vaccine efficacy and the titer of anti-Tat IgG was potentiated by BCG vaccination in Mtb-free mice. In general, Tat treatment was well tolerated in both Mtb-infected and Mtb-free mice.
  
  
  
  Tat protein vaccine, administered in Mtb-infected mice with a protocol resembling that used in the clinical trials, was safe, immunogenic, limited the lung Mtb-associated immunopathology and did not abrogate the protective efficacy of BCG. These data provide preliminary evidence for a safe use of Tat vaccine in people vaccinated with BCG and/or suffering from tuberculosis.
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, Rome, 299 00161, Italy. aurelio.cafaro@iss.it.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Cafaro
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, Rome, 299 00161, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piccaro
authors.affiliation: Institute of Pathology, University of Padua, Padua, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Altavilla
authors.affiliation: Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR) c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy.|Dipartimento di Patologia Fondazione G. Pascale IRCCS, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Gigantino
authors.affiliation: Dipartimento di Medicina e Chirurgia, Università di Salerno, Salerno, Italy.|MultiMedica IRCCS, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matarese
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, Rome, 299 00161, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Olivieri
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, Rome, 299 00161, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Ferrantelli
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena, Rome, 299 00161, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ensoli
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, Rome, 299 00161, Italy. carla.palma@iss.it.
authors.forename: Carla
authors.initials: C
authors.lastname: Palma
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000276:immunology; D058491:Bacterial Load; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015483:HIV Antibodies / Q000097:blood; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology / Q000302:isolation & purification; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D014611:Vaccination; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001500:BCG Vaccine; C496535:Ccl4 protein, mouse; D054407:Chemokine CCL4; D015483:HIV Antibodies; D020381:Interleukin-17; D053583:Interleukin-1beta; D011994:Recombinant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma
keywords: Antibodies; Cytokines; M. tuberculosis infection; Rodent; T cell responses; Tat vaccination