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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

CD38+HLA-DR+/CD8+T cells in individuals immunized with Tat at the 30 μg doses or in OBS subjects. Changes from baseline of CD38+HLA-DR+/CD8+ at years 1, 2 and 3 in (A) vaccinees of the Tat 30 μg, 3x group (year 1: n = 28; year 2: n = 20; year 3: n = 10) and the Tat 30 μg, 5x group (year 1: n = 28; year: 2 n = 19; year 3: n = 9); (B) OBS subjects (year 1: n = 38; year 2: n = 25). (C) Changes from baseline of CD38+HLA-DR+/CD8+ at week 8, 12, 20 and 48 in vaccinees of the Tat 30 μg, 3x group (n = 28); and the Tat 30 μg, 5x group (n = 28). Data are presented as mean values with standard error. A longitudinal analysis for repeated measurements was applied. P-values assess the values at year 1, 2, or 3 or week 8, 12, 20 or 48 after immunization versus baseline values.
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Fig13: CD38+HLA-DR+/CD8+T cells in individuals immunized with Tat at the 30 μg doses or in OBS subjects. Changes from baseline of CD38+HLA-DR+/CD8+ at years 1, 2 and 3 in (A) vaccinees of the Tat 30 μg, 3x group (year 1: n = 28; year 2: n = 20; year 3: n = 10) and the Tat 30 μg, 5x group (year 1: n = 28; year: 2 n = 19; year 3: n = 9); (B) OBS subjects (year 1: n = 38; year 2: n = 25). (C) Changes from baseline of CD38+HLA-DR+/CD8+ at week 8, 12, 20 and 48 in vaccinees of the Tat 30 μg, 3x group (n = 28); and the Tat 30 μg, 5x group (n = 28). Data are presented as mean values with standard error. A longitudinal analysis for repeated measurements was applied. P-values assess the values at year 1, 2, or 3 or week 8, 12, 20 or 48 after immunization versus baseline values.

Mentions: In particular, the presence of IgG and IgM anti-Tat Abs was more frequent in both the 30 μg dose regimens (60% in 30 μg, 3x group and 62% in 30 μg, 5x group) (Figure 2D), although proviral reduction was greater when Tat was given 3 times as compared to 5 times. Therefore, all immunological parameters for which data were available were compared between the two treatment groups. As shown in Figure 13 and Figure 14, the only relevant differences were found for CD38+ HLA-DR+/CD8+ T cell percentage and NK cell number. In particular, in the 30 μg, 3x group, CD38+ HLA-DR+/CD8+ T cells were significantly increased at year 1, whereas only a trend was seen in the 30 μg, 5x group, and thereafter these cells declined in both groups, particularly in the 30 μg, 5x regimen (Figure 13A). Flow cytometry data analysis indicated that the increase of CD38+HLA-DR+/CD8+ T cells was due to the upregulation of HLA-DR expression, a marker associated with proliferative capacity and found increased in elite controllers [62]. Stratification of year 1 data by weeks indicated that the increase of this cell phenotype occurred and was significant in both groups after 3 immunizations (week 12) (Figure 13C), whereas further immunizations in the 30 μg, 5x group did not increase or maintain these cells, which, in contrast, were reduced down to undetectable levels at 48 weeks (Figure 13C). Significant reductions were observed in OBS subjects upon time (Figure 13B).Figure 13


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)

CD38+HLA-DR+/CD8+T cells in individuals immunized with Tat at the 30 μg doses or in OBS subjects. Changes from baseline of CD38+HLA-DR+/CD8+ at years 1, 2 and 3 in (A) vaccinees of the Tat 30 μg, 3x group (year 1: n = 28; year 2: n = 20; year 3: n = 10) and the Tat 30 μg, 5x group (year 1: n = 28; year: 2 n = 19; year 3: n = 9); (B) OBS subjects (year 1: n = 38; year 2: n = 25). (C) Changes from baseline of CD38+HLA-DR+/CD8+ at week 8, 12, 20 and 48 in vaccinees of the Tat 30 μg, 3x group (n = 28); and the Tat 30 μg, 5x group (n = 28). Data are presented as mean values with standard error. A longitudinal analysis for repeated measurements was applied. P-values assess the values at year 1, 2, or 3 or week 8, 12, 20 or 48 after immunization versus baseline values.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig13: CD38+HLA-DR+/CD8+T cells in individuals immunized with Tat at the 30 μg doses or in OBS subjects. Changes from baseline of CD38+HLA-DR+/CD8+ at years 1, 2 and 3 in (A) vaccinees of the Tat 30 μg, 3x group (year 1: n = 28; year 2: n = 20; year 3: n = 10) and the Tat 30 μg, 5x group (year 1: n = 28; year: 2 n = 19; year 3: n = 9); (B) OBS subjects (year 1: n = 38; year 2: n = 25). (C) Changes from baseline of CD38+HLA-DR+/CD8+ at week 8, 12, 20 and 48 in vaccinees of the Tat 30 μg, 3x group (n = 28); and the Tat 30 μg, 5x group (n = 28). Data are presented as mean values with standard error. A longitudinal analysis for repeated measurements was applied. P-values assess the values at year 1, 2, or 3 or week 8, 12, 20 or 48 after immunization versus baseline values.
Mentions: In particular, the presence of IgG and IgM anti-Tat Abs was more frequent in both the 30 μg dose regimens (60% in 30 μg, 3x group and 62% in 30 μg, 5x group) (Figure 2D), although proviral reduction was greater when Tat was given 3 times as compared to 5 times. Therefore, all immunological parameters for which data were available were compared between the two treatment groups. As shown in Figure 13 and Figure 14, the only relevant differences were found for CD38+ HLA-DR+/CD8+ T cell percentage and NK cell number. In particular, in the 30 μg, 3x group, CD38+ HLA-DR+/CD8+ T cells were significantly increased at year 1, whereas only a trend was seen in the 30 μg, 5x group, and thereafter these cells declined in both groups, particularly in the 30 μg, 5x regimen (Figure 13A). Flow cytometry data analysis indicated that the increase of CD38+HLA-DR+/CD8+ T cells was due to the upregulation of HLA-DR expression, a marker associated with proliferative capacity and found increased in elite controllers [62]. Stratification of year 1 data by weeks indicated that the increase of this cell phenotype occurred and was significant in both groups after 3 immunizations (week 12) (Figure 13C), whereas further immunizations in the 30 μg, 5x group did not increase or maintain these cells, which, in contrast, were reduced down to undetectable levels at 48 weeks (Figure 13C). Significant reductions were observed in OBS subjects upon time (Figure 13B).Figure 13

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