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Fraternale A.,Urbino University | Paoletti M.F.,Urbino University | Dominici S.,Urbino University | Buondelmonte C.,Urbino University | And 11 more authors.
Vaccine | Year: 2011

We have previously demonstrated that in Ova-immunized mice the increase in intra-macrophage thiol pool induced by pro-GSH molecules modulates the Th1/Th2 balance in favour of a Th1-type immune response. We show now that the same molecules can support a Th1-type over Th2-type immunity against Tat, which is an early HIV-1 regulatory protein and a Th1 polarizing immunomodulator that is increasingly considered in new anti-HIV vaccination strategies. Our results indicate that Tat-immunized mice pre-treated with the C4 (n-butanoyl) derivative of reduced glutathione (GSH-C4) or a pro-drug of N-acetylcysteine (NAC) and beta-mercaptoethylamine (MEA) (I-152), have decreased levels of anti-Tat IgG1 as well as increased levels of anti-Tat IgG2a and IgG2b isotypes suggesting a Th1-type response. Moreover, Th1-(IFN-γ and IL-2) Ag-specific cellular responses were detected by ELISPOT assay in splenocytes of the same animals as well as an increase of IL-12 levels in the plasma. These findings suggest that the Th1 immune response to HIV-1 Tat could be further polarized by these molecules. These results together with those previously reported suggest that pro-GSH molecules could be used to modulate the immune response towards different antigens and may be further exploited for inducing specific Th1 immune responses against other HIV antigens as well as other intracellular pathogens in new Tat-based vaccination protocols. © 2011 Elsevier Ltd. Source


Chiozzini C.,Research and Evaluation | Collacchi B.,Research and Evaluation | Nappia F.,Research and Evaluation | Bauer T.,Helmholtz Center Munich | And 8 more authors.
AIDS | Year: 2014

Objective: The identification of still unrevealed mechanisms affecting the anti-HIV CD8+T- cellsresponse in HIV-1 infection. Design: Starting from the observation that anti-Tat immunization is associated with improved CD8+T- cellsimmunity, we developed both in-vitro and ex-vivo assays to characterize the effects of extra-cellular Tat on the adaptive CD8+T- cells response. Methods: The effects of Tat on CD8+T- cells activation were assayed using CD8+T- cells clones specific for either cellular (MART-1) or viral (HIV-1 Nef) antigens, and HIV-1 Gag-specific CD8 T cells from HIV-1 patients. Results: The interaction between CD8 T lymphocytes and immobilized Tat, but not its soluble form, inhibits peptide-specific CD8+T lymphocyte activation. The inhibition does not depend on Tat trans-activation activity, but on the interaction of the Tat RGD domain with α5β1 and αvβ3 integrins. Impaired CD8+T activation was also observed in cocultures of CD8+T- cells with HIV-1-infected cells. Anti-Tat Abs abrogate the inhibitory effect, consistently with the evidence that extracellular Tat accumulates on the cell membrane of virus-producing cells. The Tat-induced inhibition of cell activation associates with increased apoptosis of CD8+T- cells. Finally, the inhibition of cell activation also takes place in Gag-specific CD8+T lymphocytes from HIV-1- infected patients. Conclusion: Our results support the idea that CD8+T- cells apoptosis induced by surface-bound extracellular Tat can contribute to the dysregulation of the CD8+T- cells adaptive response against HIV as well as other pathogens present in AIDS patients. © 2014 Wolters Kluwer Health|Lippincott Williams & Wilkins. Source


Ensoli B.,National Center | Bellino S.,National Center | Tripiciano A.,National Center | Tripiciano A.,Core Laboratory of Virology and Immunology | And 40 more authors.
PLoS ONE | Year: 2010

Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4+ T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4+ and CD8+ cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4+ T cells and B cells with reduction of CD8+ T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4+ and CD8+ T cells were accompanied by increases of CD4+ and CD8+ T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis. © 2010 Ensoli et al. Source

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