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

Neutralization of Tat-mediated Env entry in DC and HIV-1 DNA in vaccinees. (A) Relationship between Tat-mediated entry of trimeric Env in DC and anti-Tat IgM (blue), IgG (red) and IgA (violet) Ab binding titers in subjects immunized with Tat 30 μg, 3x (generalized estimating equations with adjustment for repeated measures in the same patient; longitudinal samples from 31 individuals). (B) Percentage of Env entry in DC in the presence or absence of Tat in subjects immunized with Tat 30 μg, 3x at 48 weeks since the first immunization (n = 32) (Student’s t-test). Data are expressed as mean changes from baseline with standard error. (C) Inhibition of Tat-mediated Env entry in DC by anti-Tat Ab positive (n = 20) and anti-Tat Ab negative (n = 12) sera at week 48 from subjects immunized with Tat 30 μg, 3x. Of the 32 subjects evaluated, 30 were positive for anti-Tat Abs before week 48. Data are expressed as the percentage of subjects showing neutralization of Tat-mediated Env entry at 48 weeks as compared to baseline. (Fisher's Exact test) (D) Pearson correlation between anti-Tat IgM and IgG Ab titers at 48 weeks and Tat-mediated Env entry in DC at 48 weeks versus baseline in subjects immunized with Tat 30 μg, 3x (n = 32). (E) Reduction from baseline of HIV-1 DNA (log10 copies/106 CD4+ T cells) over time in sera from vaccinees (Tat 30 μg, 3x) positive for neutralization (≥50%) of Env entry in DC at week 48 since vaccination (n = 20). Data in panels are presented as mean values with standard error. Changes from baseline of HIV-1 DNA in subjects with anti-Tat Abs and neutralizing activity were evaluated with a longitudinal analysis for repeated measurements. P-values assess the values at each week after immunization versus values at baseline.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig12: Neutralization of Tat-mediated Env entry in DC and HIV-1 DNA in vaccinees. (A) Relationship between Tat-mediated entry of trimeric Env in DC and anti-Tat IgM (blue), IgG (red) and IgA (violet) Ab binding titers in subjects immunized with Tat 30 μg, 3x (generalized estimating equations with adjustment for repeated measures in the same patient; longitudinal samples from 31 individuals). (B) Percentage of Env entry in DC in the presence or absence of Tat in subjects immunized with Tat 30 μg, 3x at 48 weeks since the first immunization (n = 32) (Student’s t-test). Data are expressed as mean changes from baseline with standard error. (C) Inhibition of Tat-mediated Env entry in DC by anti-Tat Ab positive (n = 20) and anti-Tat Ab negative (n = 12) sera at week 48 from subjects immunized with Tat 30 μg, 3x. Of the 32 subjects evaluated, 30 were positive for anti-Tat Abs before week 48. Data are expressed as the percentage of subjects showing neutralization of Tat-mediated Env entry at 48 weeks as compared to baseline. (Fisher's Exact test) (D) Pearson correlation between anti-Tat IgM and IgG Ab titers at 48 weeks and Tat-mediated Env entry in DC at 48 weeks versus baseline in subjects immunized with Tat 30 μg, 3x (n = 32). (E) Reduction from baseline of HIV-1 DNA (log10 copies/106 CD4+ T cells) over time in sera from vaccinees (Tat 30 μg, 3x) positive for neutralization (≥50%) of Env entry in DC at week 48 since vaccination (n = 20). Data in panels are presented as mean values with standard error. Changes from baseline of HIV-1 DNA in subjects with anti-Tat Abs and neutralizing activity were evaluated with a longitudinal analysis for repeated measurements. P-values assess the values at each week after immunization versus values at baseline.

Mentions: Since the Tat 30 μg, 3x regimen was the most effective at reducing HIV DNA, neutralization of the entry of oligomeric Env into DC in the presence or absence of Tat [32] was assessed in this treatment group by analyzing sera at week 0 (baseline) and at week 12, 20 and 48 after immunization. This assay overcomes the problem posed by HAART interference with neutralization of HIV-1 infection [61]. Sera blocking Tat-mediated Env entry in DC by ≥50% versus baseline were indicated as neutralizing. A significant inverse relationship was observed between Tat-mediated Env entry in DC and anti-Tat Ab binding titers of all isotypes (Figure 12A), particularly at week 48 (Figure 12B). At this time, neutralization was observed in 90% of the subjects with anti-Tat Abs (Figure 12C) and correlated with both anti-Tat IgM and IgG titers (Figure 12D). Of note, the presence of anti-Tat Abs and neutralizing activity at week 48 predicted a significant reduction of HIV-1 DNA, which was consistently detected at year 2 and particularly at year 3 (Figure 12E).Figure 12


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)

Neutralization of Tat-mediated Env entry in DC and HIV-1 DNA in vaccinees. (A) Relationship between Tat-mediated entry of trimeric Env in DC and anti-Tat IgM (blue), IgG (red) and IgA (violet) Ab binding titers in subjects immunized with Tat 30 μg, 3x (generalized estimating equations with adjustment for repeated measures in the same patient; longitudinal samples from 31 individuals). (B) Percentage of Env entry in DC in the presence or absence of Tat in subjects immunized with Tat 30 μg, 3x at 48 weeks since the first immunization (n = 32) (Student’s t-test). Data are expressed as mean changes from baseline with standard error. (C) Inhibition of Tat-mediated Env entry in DC by anti-Tat Ab positive (n = 20) and anti-Tat Ab negative (n = 12) sera at week 48 from subjects immunized with Tat 30 μg, 3x. Of the 32 subjects evaluated, 30 were positive for anti-Tat Abs before week 48. Data are expressed as the percentage of subjects showing neutralization of Tat-mediated Env entry at 48 weeks as compared to baseline. (Fisher's Exact test) (D) Pearson correlation between anti-Tat IgM and IgG Ab titers at 48 weeks and Tat-mediated Env entry in DC at 48 weeks versus baseline in subjects immunized with Tat 30 μg, 3x (n = 32). (E) Reduction from baseline of HIV-1 DNA (log10 copies/106 CD4+ T cells) over time in sera from vaccinees (Tat 30 μg, 3x) positive for neutralization (≥50%) of Env entry in DC at week 48 since vaccination (n = 20). Data in panels are presented as mean values with standard error. Changes from baseline of HIV-1 DNA in subjects with anti-Tat Abs and neutralizing activity were evaluated with a longitudinal analysis for repeated measurements. P-values assess the values at each week after immunization versus values at baseline.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig12: Neutralization of Tat-mediated Env entry in DC and HIV-1 DNA in vaccinees. (A) Relationship between Tat-mediated entry of trimeric Env in DC and anti-Tat IgM (blue), IgG (red) and IgA (violet) Ab binding titers in subjects immunized with Tat 30 μg, 3x (generalized estimating equations with adjustment for repeated measures in the same patient; longitudinal samples from 31 individuals). (B) Percentage of Env entry in DC in the presence or absence of Tat in subjects immunized with Tat 30 μg, 3x at 48 weeks since the first immunization (n = 32) (Student’s t-test). Data are expressed as mean changes from baseline with standard error. (C) Inhibition of Tat-mediated Env entry in DC by anti-Tat Ab positive (n = 20) and anti-Tat Ab negative (n = 12) sera at week 48 from subjects immunized with Tat 30 μg, 3x. Of the 32 subjects evaluated, 30 were positive for anti-Tat Abs before week 48. Data are expressed as the percentage of subjects showing neutralization of Tat-mediated Env entry at 48 weeks as compared to baseline. (Fisher's Exact test) (D) Pearson correlation between anti-Tat IgM and IgG Ab titers at 48 weeks and Tat-mediated Env entry in DC at 48 weeks versus baseline in subjects immunized with Tat 30 μg, 3x (n = 32). (E) Reduction from baseline of HIV-1 DNA (log10 copies/106 CD4+ T cells) over time in sera from vaccinees (Tat 30 μg, 3x) positive for neutralization (≥50%) of Env entry in DC at week 48 since vaccination (n = 20). Data in panels are presented as mean values with standard error. Changes from baseline of HIV-1 DNA in subjects with anti-Tat Abs and neutralizing activity were evaluated with a longitudinal analysis for repeated measurements. P-values assess the values at each week after immunization versus values at baseline.
Mentions: Since the Tat 30 μg, 3x regimen was the most effective at reducing HIV DNA, neutralization of the entry of oligomeric Env into DC in the presence or absence of Tat [32] was assessed in this treatment group by analyzing sera at week 0 (baseline) and at week 12, 20 and 48 after immunization. This assay overcomes the problem posed by HAART interference with neutralization of HIV-1 infection [61]. Sera blocking Tat-mediated Env entry in DC by ≥50% versus baseline were indicated as neutralizing. A significant inverse relationship was observed between Tat-mediated Env entry in DC and anti-Tat Ab binding titers of all isotypes (Figure 12A), particularly at week 48 (Figure 12B). At this time, neutralization was observed in 90% of the subjects with anti-Tat Abs (Figure 12C) and correlated with both anti-Tat IgM and IgG titers (Figure 12D). Of note, the presence of anti-Tat Abs and neutralizing activity at week 48 predicted a significant reduction of HIV-1 DNA, which was consistently detected at year 2 and particularly at year 3 (Figure 12E).Figure 12

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