Tat is a key HIV regulatory protein produced very early after infection, prior to virus integration, and necessary for viral gene expression, cell-to-cell virus transmission and disease progression. Previous studies in natural HIV infection, indicated that the presence of a Tat-specific immune response correlates with a lower incidence and reduced risk of progression to AIDS as compared to anti-Tat negative individuals suggesting that an immune response to Tat may exert a protective role and control the progression to AIDS in vivo. Moreover, Tat is conserved in its immunogenic regions (both B and T cell) among all subtypes. subtypes. Recent data, in fact, indicate an effective cross-clade recognition of clade B strain-derived (BH-10) Tat protein from the HTLV-IIIB lab-adapted virus strain (Buttò, 2003), which was isolated about 30 years ago (Ratner, 1985), by sera from individuals infected with viruses circulating at the present in Italy and in Africa, thus reflecting the high degree of conservation of the corresponding Tat regions and providing strong formal evidence that a Tat-based vaccine may indeed be used in the different geographic areas of the world, since it is capable of inducing a broad immune response against different virus clades. Based on this rationale and on the positive results of preclinical (Cafaro, Nat Med 1999) and phase I preventive and therapeutic clinical trials with Tat protein (ISS P-001 and ISS T-001, respectively) (Ensoli AIDS 2008, Vaccine 2009; Longo Vaccine 2009; Bellino RRCT, 2009) a phase II therapeutic, open label, clinical study with Tat protein (ISS T-002, ClinicalTrials.gov NCT00751595) was sponsored by ISS and activated in 11 clinical sites in Italy in HIV-infected HAART-treated subjects (Ensoli F, Retrovirology 2015).In this study, subjects are randomized into two arms to receive 3 or 5 vaccinations monthly; each arm is composed of two treatment groups, receiving 7, 5 or 30 µg of Tat, respectively.Results obtained in 168 individuals after trial completion (48 weeks), as well as after a follow-up of 144 weeks for a subgroup of vaccines, indicated that Tat vaccination is safe, immunogenic and capable of reducing the immune dysregulation which persists despite HAART in treated individuals (Ensoli et al,PLoS ONE 2010). Anti-Tat Abs were induced in most patients (79%), with the highest frequency and durability in the Tat 30 µg groups (89%) particularly when given 3 times (92%) (Ensoli B.,PLoS ONE 2010; Ensoli F., Retrovirology 2015). Moreover, vaccination promoted a durable and significant restoration of T, B, natural killer (NK) cells, and CD4+ and CD8+ central memory subsets. Moreover, a significant reduction of blood proviral DNA was seen after week 72, particularly under PI-based regimens and with Tat 30 µg given 3 times (30 μg, 3x), reaching a predicted 70% decay after 3 years from vaccination with a half-life of 88 weeks. This decay was significantly associated with anti-Tat IgM and IgG Abs and neutralization of Tat-mediated entry of oligomeric Env in dendritic cells, which predicted HIV-1 DNA decay. Finally, the 30 μg, 3x group was the only one showing significant increases of NK cells and CD38+HLA-DR+/CD8+ T cells, a phenotype associated with increased killing activity in elite controllers (Ensoli F., Retrovirology 2015). These data indicate that Tat immunization represents a promising pathogenesis-driven intervention to intensify HAART efficacy (Ensoli et al,PLoS ONE 2010).