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

Abstract

BackgroundThe 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.ResultsThe 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.ConclusionsAnti-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0151-y) contains supplementary material, which is available to authorized users.

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“…Extracellular HIV-Tat is supposed to be essential for viral spread and plays an important role in AIDS pathogenesis by modulating the immune response (49 -51). Recent studies indicate that vaccination with anti-Tat antibodies slows down AIDS progression and may restore immune functions (52)(53)(54). Intriguingly, HIV-Tat has previously been demonstrated to exit infected T cells in a PI(4,5)P 2 -dependent manner (41,55,56).…”

HIV-Tat Protein Forms Phosphoinositide-dependent Membrane Pores Implicated in Unconventional Protein Secretion

“…Extracellular HIV-Tat is supposed to be essential for viral spread and plays an important role in AIDS pathogenesis by modulating the immune response (9,12,14). Recent studies indicate that vaccination with anti-Tat antibodies slows down AIDS progression and may restore immune functions (15)(16)(17).…”

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