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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

CD4+, CD8+, B and NK cell numbers. Changes from baseline of (A, B) CD4+, (C, D) CD8+, (E, F) B and (G, H) NK cells at years 1, 2 and 3 in vaccinees (left panels) (n = 152 at year 1 ; n = 114 at year 2 ; n = 69 at year 3) and in OBS subjects (right panels) (n = 79 at year 1 ; n = 42 at year 2 ; n = 30 at year 3), respectively. 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 after immunization versus baseline values.
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Fig4: CD4+, CD8+, B and NK cell numbers. Changes from baseline of (A, B) CD4+, (C, D) CD8+, (E, F) B and (G, H) NK cells at years 1, 2 and 3 in vaccinees (left panels) (n = 152 at year 1 ; n = 114 at year 2 ; n = 69 at year 3) and in OBS subjects (right panels) (n = 79 at year 1 ; n = 42 at year 2 ; n = 30 at year 3), respectively. 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 after immunization versus baseline values.

Mentions: A significant increase of CD4+ T cell number was observed early after Tat immunization, peaking at year 2 (up to about 100 cells/μl increase p < 0.0001) and persisting at year 3, while no significant changes from baseline were detected in OBS subjects during the 3 years of follow up (Figure 4A, B), as observed previously for successfully treated subjects after years of therapy (mean of 6 years for both ISS T-002 and OBS subjects) [51-53]. At the same time, Tat immunization maintained stable levels of CD8+ T cells, which, in contrast, progressively decreased in OBS subjects, particularly at year 2 and 3 (Figure 4C, D), as observed earlier during HAART [54-56]. An early and significant increase of B cells was also induced by Tat immunization that reached the highest value at year 3, whereas a trend to reduction was observed in OBS subjects (Figure 4E, F). Natural killer (NK) cell numbers were also significantly increased in vaccinees at year 2 and 3, while no significant changes were observed in OBS subjects (Figure 4 G, H). The pattern of B and NK cells seen in OBS is similar to what has been reported during HAART [57,58].Figure 4


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)

CD4+, CD8+, B and NK cell numbers. Changes from baseline of (A, B) CD4+, (C, D) CD8+, (E, F) B and (G, H) NK cells at years 1, 2 and 3 in vaccinees (left panels) (n = 152 at year 1 ; n = 114 at year 2 ; n = 69 at year 3) and in OBS subjects (right panels) (n = 79 at year 1 ; n = 42 at year 2 ; n = 30 at year 3), respectively. 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 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

Fig4: CD4+, CD8+, B and NK cell numbers. Changes from baseline of (A, B) CD4+, (C, D) CD8+, (E, F) B and (G, H) NK cells at years 1, 2 and 3 in vaccinees (left panels) (n = 152 at year 1 ; n = 114 at year 2 ; n = 69 at year 3) and in OBS subjects (right panels) (n = 79 at year 1 ; n = 42 at year 2 ; n = 30 at year 3), respectively. 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 after immunization versus baseline values.
Mentions: A significant increase of CD4+ T cell number was observed early after Tat immunization, peaking at year 2 (up to about 100 cells/μl increase p < 0.0001) and persisting at year 3, while no significant changes from baseline were detected in OBS subjects during the 3 years of follow up (Figure 4A, B), as observed previously for successfully treated subjects after years of therapy (mean of 6 years for both ISS T-002 and OBS subjects) [51-53]. At the same time, Tat immunization maintained stable levels of CD8+ T cells, which, in contrast, progressively decreased in OBS subjects, particularly at year 2 and 3 (Figure 4C, D), as observed earlier during HAART [54-56]. An early and significant increase of B cells was also induced by Tat immunization that reached the highest value at year 3, whereas a trend to reduction was observed in OBS subjects (Figure 4E, F). Natural killer (NK) cell numbers were also significantly increased in vaccinees at year 2 and 3, while no significant changes were observed in OBS subjects (Figure 4 G, H). The pattern of B and NK cells seen in OBS is similar to what has been reported during HAART [57,58].Figure 4

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