HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial

Retrovirology

Barbara Ensoli¹  Enrico Garaci^1,13  Mauro Magnani⁴  Paolo Monini¹  Giovanni Di Perri^1,10  Francesco Castelli⁸  Vito S Mercurio^1,14  Massimo Galli^1,15  Massimo Di Pietro⁹  Gioacchino Angarano³  Andrea Gori²  Guido Palamara^1,12  Laura Sighinolfi⁵  Adriano Lazzarin⁷  Cristina Mussini⁶  Giovanni Paniccia¹  Maria T Maggiorella¹  Leonardo Sernicola¹  Chiara Orlandi⁴  Angela Arancio¹  Maria R Pavone Cossut¹  Sonia Moretti¹  Cecilia Sgadari¹  Orietta Picconi¹  Vittorio Francavilla¹  Olimpia Longo¹  Stefania Bellino¹  Antonella Tripiciano¹  Anna Casabianca⁴  Aurelio Cafaro¹  Fabrizio Ensoli^1,11 

[1] National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy;Division of Infectious Diseases, San Gerardo Hospital, Monza, Italy;Division of Infectious Diseases, University of Bari, Policlinic Hospital, Bari, Italy;Department of Biomolecular Science, University of Urbino, Urbino, Italy;Unit of Infectious Diseases, University Hospital of Ferrara, Ferrara, Italy;Division of Infectious Diseases, University Policlinic of Modena, Modena, Italy;Division of Infectious Diseases, S. Raffaele Hospital, Milan, Italy;Division of Tropical and Infectious Diseases, Spedali Civili, Brescia, Italy;Unit of Infectious Diseases, S.M. Annunziata Hospital, Florence, Italy;Clinic of Infectious Diseases, Amedeo di Savoia Hospital, Turin, Italy;Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy;Department of Infectious Dermatology, San Gallicano Hospital, Rome, Italy;Istituto Superiore di Sanità, Rome, Italy, present address University of Tor Vergata, Rome 00173, Italy;Department of Infectious Diseases, S. Maria Goretti Hospital, Latina, Italy;Institute of Tropical and Infectious Diseases, L. Sacco Hospital, University of Milan, Milan, Italy

关键词: CD38+HLA-DR+/CD8+ T cells;    Proviral DNA;    Neutralization;    Antibodies;    HAART;    Vaccine;    Tat protein;    HIV-1;   

Others  :  1210153
DOI  :  10.1186/s12977-015-0151-y

 received in 2014-10-16, accepted in 2015-02-11,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Ensoli et al.; licensee BioMed Central.

【 图 表 】

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