Abstract
BackgroundThe 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.MethodsC57BL/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.ResultsIn 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.ConclusionsTat 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.
Highlights
The therapeutic HIV-1 Tat protein vaccine is in advanced clinical development
Protection against Mycobacterium tuberculosis (Mtb) infection conferred by the Bacillus Calmette-Guerin (BCG) vaccine remains good in mice receiving Tat protein vaccine We evaluated whether the administration of Tat vaccine could alter the protection conferred by BCG, the gold standard TB vaccine
Administration of Tat vaccine enhances mycobacterialspecific IFN-γ and IL-17 responses in mice infected with Mtb and in Mtb-free mice vaccinated with BCG We evaluated the effect of Tat vaccination on the development of systemic Mtb-specific immune responses, focusing on IFN-γ, which is essential for control of Mtb infection [26, 27] and IL-17, which appears to play a protective role in the early phase of Mtb infection [28]
Summary
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. Two different trials indicated that Tat vaccine contributed to HIV-1 containment in patients on effective HAART [14, 18], (ISS T-003, ClinicalTrial.gov identifier: NCT01513135). A confirmatory phase II, randomized, doubleblind, placebo-controlled trial in HIV-infected, anti-Tat antibody negative, antiretroviral-treated adult volunteers [18], (ISS T-003, ClinicalTrial.gov identifier: NCT01513135) has been completed in South Africa, an endemic region in which approximately 28 % of individuals living with HIV and tuberculosis (TB) reside [19]. It is of relevance to verify whether vaccines or immunotherapies against HIV infections can be safely administered to individuals infected by Mtb. the lack of this information has prevented enrollment of HIV-1 infected individuals with active TB in the Tat vaccine therapeutic trial conducted in South Africa [18], (ISS T-003, ClinicalTrial.gov identifier: NCT01513135)
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