Therapeutic immunization with hiv-1 tat reduces immune activation and loss of regulatory t-cells and improves immune function in subjects on HAART

Barbara Ensoli, Stefania Bellino, Antonella Tripiciano, Olimpia Longo, Vittorio Francavilla, Simone Marcotullio, Aurelio Cafaro, Orietta Picconi, Giovanni Paniccia, Arianna Scoglio, Angela Arancio, Cristina Ariola, Maria J. Ruiz Alvarez, Massimo Campagna, Donato Scaramuzzi, Cristina Iori, Roberto Esposito, Cristina Mussini, Florio Ghinelli, Laura SighinolfiGuido Palamara, Alessandra Latini, Gioacchino Angarano, Nicoletta Ladisa, Fabrizio Soscia, Vito S. Mercurio, Adriano Lazzarin, Giuseppe Tambussi, Raffaele Visintini, Francesco Mazzotta, Massimo Di Pietro, Massimo Galli, Stefano Rusconi, Giampiero Carosi, Carlo Torti, Giovanni Di Perri, Stefano Bonora, Fabrizio Ensoli, Enrico Garaci

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article numbere13540
JournalPLoS One
Volume5
Issue number11
DOIs
Publication statusPublished - 2010

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Ensoli, B., Bellino, S., Tripiciano, A., Longo, O., Francavilla, V., Marcotullio, S., Cafaro, A., Picconi, O., Paniccia, G., Scoglio, A., Arancio, A., Ariola, C., Ruiz Alvarez, M. J., Campagna, M., Scaramuzzi, D., Iori, C., Esposito, R., Mussini, C., Ghinelli, F., ... Garaci, E. (2010). Therapeutic immunization with hiv-1 tat reduces immune activation and loss of regulatory t-cells and improves immune function in subjects on HAART. PLoS One, 5(11), [e13540]. https://doi.org/10.1371/journal.pone.0013540