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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

Anti-Tat cellular immune response. IFN-γ, IL-2 or IL-4 production and CD4+ or CD8+ T cell proliferation to Tat in (A) vaccinees or (C) OBS subjects. The percentages of responders at baseline (white bars) and up to 48 weeks from baseline (blue bars) (vaccinees: IFN-γ, IL-2, or IL-4 n = 151, proliferation n = 140; OBS: IFN-γ, IL-2, or IL-4 n = 60, proliferation n = 54) are shown. Peak intensity of anti-Tat cellular responses in (B) vaccinees or (D) OBS subjects at baseline (white bars) and up to 48 weeks (blue bars) in responders (subjects with at least one positive response after baseline) (vaccinees: IFN-γ n = 39, IL-2 n = 38, IL-4 n = 12, CD4+ proliferation n = 86, CD8+ proliferation n = 77; OBS: IFN-γ n = 12, IL-2 n = 11, IL-4 n = 6, CD4+ proliferation n = 33, CD8+ proliferation n = 34). Box plots represent the median, 25th and 75th percentile, with the minimum and maximum values; the outliers are not represented in the graphs. The McNemar’s and Wilcoxon signed-rank tests were applied. P-values assess the values of frequencies and intensity, respectively, up to 48 weeks after immunization versus baseline values.
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Fig3: Anti-Tat cellular immune response. IFN-γ, IL-2 or IL-4 production and CD4+ or CD8+ T cell proliferation to Tat in (A) vaccinees or (C) OBS subjects. The percentages of responders at baseline (white bars) and up to 48 weeks from baseline (blue bars) (vaccinees: IFN-γ, IL-2, or IL-4 n = 151, proliferation n = 140; OBS: IFN-γ, IL-2, or IL-4 n = 60, proliferation n = 54) are shown. Peak intensity of anti-Tat cellular responses in (B) vaccinees or (D) OBS subjects at baseline (white bars) and up to 48 weeks (blue bars) in responders (subjects with at least one positive response after baseline) (vaccinees: IFN-γ n = 39, IL-2 n = 38, IL-4 n = 12, CD4+ proliferation n = 86, CD8+ proliferation n = 77; OBS: IFN-γ n = 12, IL-2 n = 11, IL-4 n = 6, CD4+ proliferation n = 33, CD8+ proliferation n = 34). Box plots represent the median, 25th and 75th percentile, with the minimum and maximum values; the outliers are not represented in the graphs. The McNemar’s and Wilcoxon signed-rank tests were applied. P-values assess the values of frequencies and intensity, respectively, up to 48 weeks after immunization versus baseline values.

Mentions: In the Tat 30 μg groups Abs persisted significantly longer, as compared to the Tat 7.5 μg groups (Figure 2B). The 30 μg doses were also more effective at inducing anti-Tat Abs of different isotypes (Figure 2C, D), and peak IgG titers (Figure 2E, F). Tat immunization also increased the percentage of responders and intensity of anti-Tat cellular responses, including IFN-γ, IL-4, IL-2 production and CD4+-, CD8+-T cell proliferation, as compared to baseline (Table 6 and Figure 3A, B) without significant differences among the treatment groups. Cellular responses to Tat were also present in OBS subjects (Figure 3C, D).Figure 3


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)

Anti-Tat cellular immune response. IFN-γ, IL-2 or IL-4 production and CD4+ or CD8+ T cell proliferation to Tat in (A) vaccinees or (C) OBS subjects. The percentages of responders at baseline (white bars) and up to 48 weeks from baseline (blue bars) (vaccinees: IFN-γ, IL-2, or IL-4 n = 151, proliferation n = 140; OBS: IFN-γ, IL-2, or IL-4 n = 60, proliferation n = 54) are shown. Peak intensity of anti-Tat cellular responses in (B) vaccinees or (D) OBS subjects at baseline (white bars) and up to 48 weeks (blue bars) in responders (subjects with at least one positive response after baseline) (vaccinees: IFN-γ n = 39, IL-2 n = 38, IL-4 n = 12, CD4+ proliferation n = 86, CD8+ proliferation n = 77; OBS: IFN-γ n = 12, IL-2 n = 11, IL-4 n = 6, CD4+ proliferation n = 33, CD8+ proliferation n = 34). Box plots represent the median, 25th and 75th percentile, with the minimum and maximum values; the outliers are not represented in the graphs. The McNemar’s and Wilcoxon signed-rank tests were applied. P-values assess the values of frequencies and intensity, respectively, up to 48 weeks after immunization versus baseline values.
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Related In: Results  -  Collection

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Fig3: Anti-Tat cellular immune response. IFN-γ, IL-2 or IL-4 production and CD4+ or CD8+ T cell proliferation to Tat in (A) vaccinees or (C) OBS subjects. The percentages of responders at baseline (white bars) and up to 48 weeks from baseline (blue bars) (vaccinees: IFN-γ, IL-2, or IL-4 n = 151, proliferation n = 140; OBS: IFN-γ, IL-2, or IL-4 n = 60, proliferation n = 54) are shown. Peak intensity of anti-Tat cellular responses in (B) vaccinees or (D) OBS subjects at baseline (white bars) and up to 48 weeks (blue bars) in responders (subjects with at least one positive response after baseline) (vaccinees: IFN-γ n = 39, IL-2 n = 38, IL-4 n = 12, CD4+ proliferation n = 86, CD8+ proliferation n = 77; OBS: IFN-γ n = 12, IL-2 n = 11, IL-4 n = 6, CD4+ proliferation n = 33, CD8+ proliferation n = 34). Box plots represent the median, 25th and 75th percentile, with the minimum and maximum values; the outliers are not represented in the graphs. The McNemar’s and Wilcoxon signed-rank tests were applied. P-values assess the values of frequencies and intensity, respectively, up to 48 weeks after immunization versus baseline values.
Mentions: In the Tat 30 μg groups Abs persisted significantly longer, as compared to the Tat 7.5 μg groups (Figure 2B). The 30 μg doses were also more effective at inducing anti-Tat Abs of different isotypes (Figure 2C, D), and peak IgG titers (Figure 2E, F). Tat immunization also increased the percentage of responders and intensity of anti-Tat cellular responses, including IFN-γ, IL-4, IL-2 production and CD4+-, CD8+-T cell proliferation, as compared to baseline (Table 6 and Figure 3A, B) without significant differences among the treatment groups. Cellular responses to Tat were also present in OBS subjects (Figure 3C, D).Figure 3

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