Limits...
HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial.

Ensoli F, Cafaro A, Casabianca A, Tripiciano A, Bellino S, Longo O, Francavilla V, Picconi O, Sgadari C, Moretti S, Cossut MR, Arancio A, Orlandi C, Sernicola L, Maggiorella MT, Paniccia G, Mussini C, Lazzarin A, Sighinolfi L, Palamara G, Gori A, Angarano G, Di Pietro M, Galli M, Mercurio VS, Castelli F, Di Perri G, Monini P, Magnani M, Garaci E, Ensoli B - Retrovirology (2015)

Bottom Line: 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.Anti-Tat immune responses are needed to restore immune homeostasis and effective anti-viral responses capable of attacking the virus reservoir.

View Article: PubMed Central - PubMed

Affiliation: Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy. ensoli@ifo.it.

ABSTRACT

Background: The phase II multicenter, randomized, open label, therapeutic trial (ISS T-002, Clinicaltrials.gov NCT00751595) was aimed at evaluating the immunogenicity and the safety of the biologically active HIV-1 Tat protein administered at 7.5 or 30 μg, given 3 or 5 times monthly, and at exploring immunological and virological disease biomarkers. The study duration was 48 weeks, however, vaccinees were followed until the last enrolled subject reached the 48 weeks. Reported are final data up to 144 weeks of follow-up. The ISS T-002 trial was conducted in 11 clinical centers in Italy on 168 HIV positive subjects under Highly Active Antiretroviral Therapy (HAART), anti-Tat Antibody (Ab) negative at baseline, with plasma viremia <50 copies/mL in the last 6 months prior to enrollment, and CD4(+) T-cell number ≥200 cells/μL. Subjects from a parallel observational study (ISS OBS T-002, Clinicaltrials.gov NCT0102455) enrolled at the same clinical sites with the 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 μg 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 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.

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.

Show MeSH

Related in: MedlinePlus

Blood HIV-1 DNA load (expressed as log10copies/106CD4+T cells) stratified by antiretroviral regimens. (A) Changes of HIV-1 DNA (expressed as log10 copies/106 CD4+ T cells) in vaccinees (NNRTI- or NRTI-based n = 97; PI-based n = 45) or OBS subjects (NNRTI- or NRTI-based n = 30; PI-based n = 24). (B) Changes of HIV-1 DNA in vaccinees of each treatment group stratified according to ARV regimens (7.5 μg, 3x n = 36; 7.5 μg, 5x n = 36; 30 μg, 3x n = 36; 30 μg, 5x n = 34). The dotted lines represent the 99% confidence interval of HIV-1 DNA mean change from baseline (−0.24, 0.02 log10 copies/106 CD4+ T cells) in OBS subjects (all time points). In all panels data are presented as mean values with standard error. Median time of follow-up was 96 weeks for vaccinees and 120 weeks for OBS subjects. A longitudinal analysis for repeated measurements was applied. P-values assess the values at each week after immunization versus baseline values stratified by drug regimens (NNRTI/NRTI- or PI-based).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4414440&req=5

Fig10: Blood HIV-1 DNA load (expressed as log10copies/106CD4+T cells) stratified by antiretroviral regimens. (A) Changes of HIV-1 DNA (expressed as log10 copies/106 CD4+ T cells) in vaccinees (NNRTI- or NRTI-based n = 97; PI-based n = 45) or OBS subjects (NNRTI- or NRTI-based n = 30; PI-based n = 24). (B) Changes of HIV-1 DNA in vaccinees of each treatment group stratified according to ARV regimens (7.5 μg, 3x n = 36; 7.5 μg, 5x n = 36; 30 μg, 3x n = 36; 30 μg, 5x n = 34). The dotted lines represent the 99% confidence interval of HIV-1 DNA mean change from baseline (−0.24, 0.02 log10 copies/106 CD4+ T cells) in OBS subjects (all time points). In all panels data are presented as mean values with standard error. Median time of follow-up was 96 weeks for vaccinees and 120 weeks for OBS subjects. A longitudinal analysis for repeated measurements was applied. P-values assess the values at each week after immunization versus baseline values stratified by drug regimens (NNRTI/NRTI- or PI-based).

Mentions: Since CD4+ T cells harbor most of the provirus detectable in blood [46], HIV-1 DNA was then calculated according to CD4+ T cell counts. As shown in Figure 10A, the percentage of proviral reduction in all vaccinees under PI-based regimens ranged from 26% (week 48) to 60% (week 132), and in the Tat 30 μg, 3x under PI-based regimens ranged from 53% (week 72) to 85%, (week 144), followed by Tat 7.5 μg, 5x (range from 53% to 67%, at week 84 and 108, respectively) and Tat 30 μg, 5x (range from 31% to 47%, at week 96 and 72, respectively) (Figure 10B). Conversely, lower and transient reductions were seen in the 7.5 μg, 3x group and in OBS subjects, and were mostly observed under PI-based regimens. The changes of proviral load in OBS recapitulate what previously reported under successful therapy [59,60].Figure 10


HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial.

Ensoli F, Cafaro A, Casabianca A, Tripiciano A, Bellino S, Longo O, Francavilla V, Picconi O, Sgadari C, Moretti S, Cossut MR, Arancio A, Orlandi C, Sernicola L, Maggiorella MT, Paniccia G, Mussini C, Lazzarin A, Sighinolfi L, Palamara G, Gori A, Angarano G, Di Pietro M, Galli M, Mercurio VS, Castelli F, Di Perri G, Monini P, Magnani M, Garaci E, Ensoli B - Retrovirology (2015)

Blood HIV-1 DNA load (expressed as log10copies/106CD4+T cells) stratified by antiretroviral regimens. (A) Changes of HIV-1 DNA (expressed as log10 copies/106 CD4+ T cells) in vaccinees (NNRTI- or NRTI-based n = 97; PI-based n = 45) or OBS subjects (NNRTI- or NRTI-based n = 30; PI-based n = 24). (B) Changes of HIV-1 DNA in vaccinees of each treatment group stratified according to ARV regimens (7.5 μg, 3x n = 36; 7.5 μg, 5x n = 36; 30 μg, 3x n = 36; 30 μg, 5x n = 34). The dotted lines represent the 99% confidence interval of HIV-1 DNA mean change from baseline (−0.24, 0.02 log10 copies/106 CD4+ T cells) in OBS subjects (all time points). In all panels data are presented as mean values with standard error. Median time of follow-up was 96 weeks for vaccinees and 120 weeks for OBS subjects. A longitudinal analysis for repeated measurements was applied. P-values assess the values at each week after immunization versus baseline values stratified by drug regimens (NNRTI/NRTI- or PI-based).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4414440&req=5

Fig10: Blood HIV-1 DNA load (expressed as log10copies/106CD4+T cells) stratified by antiretroviral regimens. (A) Changes of HIV-1 DNA (expressed as log10 copies/106 CD4+ T cells) in vaccinees (NNRTI- or NRTI-based n = 97; PI-based n = 45) or OBS subjects (NNRTI- or NRTI-based n = 30; PI-based n = 24). (B) Changes of HIV-1 DNA in vaccinees of each treatment group stratified according to ARV regimens (7.5 μg, 3x n = 36; 7.5 μg, 5x n = 36; 30 μg, 3x n = 36; 30 μg, 5x n = 34). The dotted lines represent the 99% confidence interval of HIV-1 DNA mean change from baseline (−0.24, 0.02 log10 copies/106 CD4+ T cells) in OBS subjects (all time points). In all panels data are presented as mean values with standard error. Median time of follow-up was 96 weeks for vaccinees and 120 weeks for OBS subjects. A longitudinal analysis for repeated measurements was applied. P-values assess the values at each week after immunization versus baseline values stratified by drug regimens (NNRTI/NRTI- or PI-based).
Mentions: Since CD4+ T cells harbor most of the provirus detectable in blood [46], HIV-1 DNA was then calculated according to CD4+ T cell counts. As shown in Figure 10A, the percentage of proviral reduction in all vaccinees under PI-based regimens ranged from 26% (week 48) to 60% (week 132), and in the Tat 30 μg, 3x under PI-based regimens ranged from 53% (week 72) to 85%, (week 144), followed by Tat 7.5 μg, 5x (range from 53% to 67%, at week 84 and 108, respectively) and Tat 30 μg, 5x (range from 31% to 47%, at week 96 and 72, respectively) (Figure 10B). Conversely, lower and transient reductions were seen in the 7.5 μg, 3x group and in OBS subjects, and were mostly observed under PI-based regimens. The changes of proviral load in OBS recapitulate what previously reported under successful therapy [59,60].Figure 10

Bottom Line: 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.Anti-Tat immune responses are needed to restore immune homeostasis and effective anti-viral responses capable of attacking the virus reservoir.

View Article: PubMed Central - PubMed

Affiliation: Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy. ensoli@ifo.it.

ABSTRACT

Background: The phase II multicenter, randomized, open label, therapeutic trial (ISS T-002, Clinicaltrials.gov NCT00751595) was aimed at evaluating the immunogenicity and the safety of the biologically active HIV-1 Tat protein administered at 7.5 or 30 μg, given 3 or 5 times monthly, and at exploring immunological and virological disease biomarkers. The study duration was 48 weeks, however, vaccinees were followed until the last enrolled subject reached the 48 weeks. Reported are final data up to 144 weeks of follow-up. The ISS T-002 trial was conducted in 11 clinical centers in Italy on 168 HIV positive subjects under Highly Active Antiretroviral Therapy (HAART), anti-Tat Antibody (Ab) negative at baseline, with plasma viremia <50 copies/mL in the last 6 months prior to enrollment, and CD4(+) T-cell number ≥200 cells/μL. Subjects from a parallel observational study (ISS OBS T-002, Clinicaltrials.gov NCT0102455) enrolled at the same clinical sites with the 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 μg 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 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.

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.

Show MeSH
Related in: MedlinePlus