Ensoli Fabrizio, Cafaro Aurelio, Casabianca Anna, Tripiciano Antonella, Bellino Stefania, Longo Olimpia, Francavilla Vittorio, Picconi Orietta, Sgadari Cecilia, Moretti Sonia, Cossut Maria R Pavone, Arancio Angela, Orlandi Chiara, Sernicola Leonardo, Maggiorella Maria T, Paniccia Giovanni, Mussini Cristina, Lazzarin Adriano, Sighinolfi Laura, Palamara Guido, Gori Andrea, Angarano Gioacchino, Di Pietro Massimo, Galli Massimo, Mercurio Vito S, Castelli Francesco, Di Perri Giovanni, Monini Paolo, Magnani Mauro, Garaci Enrico, Ensoli Barbara
Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy.
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy.
Retrovirology. 2015 Apr 29;12:33. doi: 10.1186/s12977-015-0151-y.
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.
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.
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.
II期多中心、随机、开放标签治疗性试验（ISS T - 002，Clinicaltrials.gov NCT00751595）旨在评估以7.5μg或30μg剂量、每月给药3次或5次的具有生物活性的HIV - 1 Tat蛋白的免疫原性和安全性，并探索免疫和病毒学疾病生物标志物。研究持续时间为48周，然而，对疫苗接种者进行随访，直到最后一名入组受试者达到48周。报告的是长达144周随访的最终数据。ISS T - 002试验在意大利的11个临床中心对168名HIV阳性受试者进行，这些受试者接受高效抗逆转录病毒治疗（HAART），基线时抗Tat抗体（Ab）阴性，在入组前最后6个月血浆病毒血症<50拷贝/mL，且CD4(+) T细胞数≥200细胞/μL。来自平行观察性研究（ISS OBS T - 002，Clinicaltrials.gov NCT0102455）、在相同临床地点按相同标准入组的受试者构成一个外部参考组，以探索疾病生物标志物。
该疫苗安全且耐受性良好，在大多数患者（79%）中诱导产生了抗Tat抗体，在Tat 30μg组中频率和持久性最高（89%），尤其是给药3次时（92%）。疫苗接种促进了T细胞、B细胞、自然杀伤（NK）细胞以及CD4(+)和CD8(+)中央记忆亚群的持久且显著恢复。此外，在第72周后血液中前病毒DNA显著减少，特别是在基于蛋白酶抑制剂（PI）的治疗方案下以及给予3次30μg Tat（30μg，3x）时，接种疫苗3年后预测衰减70%，半衰期为88周。这种衰减与抗Tat IgM和IgG抗体以及Tat介导的寡聚Env进入树突状细胞的中和作用显著相关，后者可预测HIV - 1 DNA衰减。最后，30μg，3x组是唯一显示NK细胞和CD38(+)HLA - DR(+)/CD8(+) T细胞显著增加的组，这种表型与精英控制者中增加的杀伤活性相关。
需要抗Tat免疫反应来恢复免疫稳态以及产生能够攻击病毒储存库的有效抗病毒反应。因此，Tat免疫接种代表了一种有前景的、以发病机制为导向的干预措施，可增强HAART的疗效。
