Ladisa (Division of Infectious Diseases, University of Bari, Policlinic Hospital, Bari, Italy), F. OBS T-002, Clinicaltrials.gov NCT0102455) enrolled at the same clinical sites with the Rabbit Polyclonal to MMP23 (Cleaved-Tyr79) same criteria constituted an external reference group to explore biomarkers of disease. Results The vaccine was safe and well tolerated and induced anti-Tat Abs in most patients (79%), with the highest frequency and durability in the Tat 30?g groups (89%) particularly when given 3 times (92%). 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?g given 3 times (30?g, 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?g, 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. Conclusions Anti-Tat immune responses are needed to restore immune homeostasis and effective anti-viral responses capable of attacking the virus reservoir. Thus, Tat immunization represents a promising pathogenesis-driven intervention to intensify HAART efficacy. Electronic supplementary material The online version of this article (doi:10.1186/s12977-015-0151-y) contains supplementary material, which is available to authorized users. indicates the number of evaluable individuals; aStandard deviation; bFive subjects had values 50 copies/ml (between 58 and 91); cFour subjects had values 50 copies/ml (between 64 and 118); d indicates the number of individuals; aStandard deviation; b indicates the number of evaluable individuals; aStandard deviation. No significant differences were detected among treatment groups at baseline. Table 4 Immunological and virological parameters at baseline in ISS T-002 and ISS OBS T-002 study participants indicates the number of individuals evaluable for each parameter according to residual specimen availability, since they were part of second line laboratory testing”. aStandard deviation; b indicates the number of individuals evaluable for each parameter according to residual specimen availability, since they were part of second line laboratory testing”. aStandard deviation; b indicates the number of individuals evaluable for each parameter. aConfidence interval; bLogistic regression model; cMantel-Haenszel Chi-Square test. Open in a separate window Figure 2 Anti-Tat humoral immune response in vaccinees. (A) Percentage of subjects producing Anti-Tat Abs (responders) after Tat immunization (7.5?g, 3x n?=?40; 7.5?g, 5x n?=?40; 30?g, 3x n?=?38; 30?g, 5x n?=?37). (B) Kaplan-Meier estimates showing the cumulative probability of anti-Tat Ab durability in responders stratified according to treatment groups and up to week 144 of follow-up (n?=?123, median follow-up of Hydroflumethiazide 96 weeks). (C) Percentage of subjects in each treatment group producing anti-Tat IgM (light blue), IgG (red), or IgA (white) Abs. (D) Percentage of subjects in each treatment group producing two (IgM and IgG, in blue) or three (IgM, IgG and IgA, in red) anti-Tat Ab classes. (E) Anti-Tat IgM (light blue) and IgA (white) peak titers between 4 and 24 weeks since the first immunization in subjects positive for IgM (7.5?g, 3x n?=?16; 7.5?g, 5x n?=?20; 30?g, 3x n?=?24; 30?g, 5x n?=?23) or IgA anti-Tat Abs (7.5?g, 3x n?=?7; 7.5?g, 5x n?=?9; 30?g, 3x n?=?19; 30?g, Hydroflumethiazide 5x n?=?22). (F) Anti-Tat IgG Ab peak titers between 4 Hydroflumethiazide and 24 weeks since the first immunization in subjects positive for IgG anti-Tat Abs (7.5?g, 3x n?=?24; 7.5?g, 5x n?=?24; 30?g, 3x n?=?32; 30?g, 5x n?=?31). Box plots represent the median, 25th and 75th percentile, with the minimum and maximum values; the outliers are not represented in the graphs. In the Tat 30?g groups Abs persisted significantly longer, as compared to the Tat 7.5?g groups (Figure?2B). The.