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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.

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Related in: MedlinePlus

HIV-1 DNA decay in individuals immunized with Tat at 30 μg, 3x or OBS subjects. (A) Longitudinal regression analysis of HIV-1 DNA (log10 copies/106 CD4+ T cells) using a random-effect regression model up to 144 weeks since the first immunization in vaccinees (Tat 30 μg, 3x, n = 37) or OBS subjects (n = 62). All longitudinal data were included in the analysis with a median of 108 weeks of follow-up in vaccinees and 120 weeks in OBS subjects, respectively. (B) Estimates of HIV-1 DNA decay based on the regression model after 1, 2 and 3 years since the first immunization in vaccinees (Tat 30 μg, 3x in red) and in OBS subjects (in blue). (C) Estimates of HIV-1 DNA annual decay in vaccinees immunized with Tat 30 μg, 3x stratified according to NNRTI- or NRTI-based (in blue, n = 25) or PI-based (in red, n = 12) regimens. Results in panels B and C are expressed as the percentage of HIV-1 DNA decay with 95% confidence interval (CI).
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Fig11: HIV-1 DNA decay in individuals immunized with Tat at 30 μg, 3x or OBS subjects. (A) Longitudinal regression analysis of HIV-1 DNA (log10 copies/106 CD4+ T cells) using a random-effect regression model up to 144 weeks since the first immunization in vaccinees (Tat 30 μg, 3x, n = 37) or OBS subjects (n = 62). All longitudinal data were included in the analysis with a median of 108 weeks of follow-up in vaccinees and 120 weeks in OBS subjects, respectively. (B) Estimates of HIV-1 DNA decay based on the regression model after 1, 2 and 3 years since the first immunization in vaccinees (Tat 30 μg, 3x in red) and in OBS subjects (in blue). (C) Estimates of HIV-1 DNA annual decay in vaccinees immunized with Tat 30 μg, 3x stratified according to NNRTI- or NRTI-based (in blue, n = 25) or PI-based (in red, n = 12) regimens. Results in panels B and C are expressed as the percentage of HIV-1 DNA decay with 95% confidence interval (CI).

Mentions: The longitudinal regression analysis confirmed the HIV-1 DNA decay in the Tat 30 μg, 3x group, but not in OBS subjects, with an estimate of 56% reduction after 3 years from vaccination (Figure 11A, B). The decay was more pronounced under PI-based regimens for which the estimate reached over 70% reduction after 3 years, with a half-life of 88 weeks (Figure 11C).Figure 11


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)

HIV-1 DNA decay in individuals immunized with Tat at 30 μg, 3x or OBS subjects. (A) Longitudinal regression analysis of HIV-1 DNA (log10 copies/106 CD4+ T cells) using a random-effect regression model up to 144 weeks since the first immunization in vaccinees (Tat 30 μg, 3x, n = 37) or OBS subjects (n = 62). All longitudinal data were included in the analysis with a median of 108 weeks of follow-up in vaccinees and 120 weeks in OBS subjects, respectively. (B) Estimates of HIV-1 DNA decay based on the regression model after 1, 2 and 3 years since the first immunization in vaccinees (Tat 30 μg, 3x in red) and in OBS subjects (in blue). (C) Estimates of HIV-1 DNA annual decay in vaccinees immunized with Tat 30 μg, 3x stratified according to NNRTI- or NRTI-based (in blue, n = 25) or PI-based (in red, n = 12) regimens. Results in panels B and C are expressed as the percentage of HIV-1 DNA decay with 95% confidence interval (CI).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig11: HIV-1 DNA decay in individuals immunized with Tat at 30 μg, 3x or OBS subjects. (A) Longitudinal regression analysis of HIV-1 DNA (log10 copies/106 CD4+ T cells) using a random-effect regression model up to 144 weeks since the first immunization in vaccinees (Tat 30 μg, 3x, n = 37) or OBS subjects (n = 62). All longitudinal data were included in the analysis with a median of 108 weeks of follow-up in vaccinees and 120 weeks in OBS subjects, respectively. (B) Estimates of HIV-1 DNA decay based on the regression model after 1, 2 and 3 years since the first immunization in vaccinees (Tat 30 μg, 3x in red) and in OBS subjects (in blue). (C) Estimates of HIV-1 DNA annual decay in vaccinees immunized with Tat 30 μg, 3x stratified according to NNRTI- or NRTI-based (in blue, n = 25) or PI-based (in red, n = 12) regimens. Results in panels B and C are expressed as the percentage of HIV-1 DNA decay with 95% confidence interval (CI).
Mentions: The longitudinal regression analysis confirmed the HIV-1 DNA decay in the Tat 30 μg, 3x group, but not in OBS subjects, with an estimate of 56% reduction after 3 years from vaccination (Figure 11A, B). The decay was more pronounced under PI-based regimens for which the estimate reached over 70% reduction after 3 years, with a half-life of 88 weeks (Figure 11C).Figure 11

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