Cafaro Aurelio, Tripiciano Antonella, Picconi Orietta, Sgadari Cecilia, Moretti Sonia, Buttò Stefano, Monini Paolo, Ensoli Barbara
National HIV/AIDS Research Center, Istituto Superiore di Sanità, Rome 00161, Italy.
Vaccines (Basel). 2019 Aug 26;7(3):99. doi: 10.3390/vaccines7030099.
HIV-1 Tat is an essential protein in the virus life cycle, which is required for virus gene expression and replication. Most Tat that is produced during infection is released extracellularly and it plays a key role in HIV pathogenesis, including residual disease upon combination antiretroviral therapy (cART). Here, we review epidemiological and experimental evidence showing that antibodies against HIV-1 Tat, infrequently occurring in natural infection, play a protective role against disease progression, and that vaccine targeting Tat can intensify cART. In fact, Tat vaccination of subjects on suppressive cART in Italy and South Africa promoted immune restoration, including CD4+ T-cell increase in low immunological responders, and a reduction of proviral DNA even after six years of cART, when both CD4+ T-cell gain and DNA decay have reached a plateau. Of note, DNA decay was predicted by the neutralization of Tat-mediated entry of Env into dendritic cells by anti-Tat antibodies, which were cross-clade binding and neutralizing. Anti-Tat cellular immunity also contributed to the DNA decay. Based on these data, we propose the Tat therapeutic vaccine as a pathogenesis-driven intervention that effectively intensifies cART and it may lead to a functional cure, providing new perspectives and opportunities also for prevention and virus eradication strategies.
HIV-1反式激活因子（Tat）是病毒生命周期中的一种必需蛋白质，是病毒基因表达和复制所必需的。感染期间产生的大多数Tat会释放到细胞外，它在HIV发病机制中起关键作用，包括联合抗逆转录病毒疗法（cART）后的残留疾病。在这里，我们综述了流行病学和实验证据，表明针对HIV-1 Tat的抗体在自然感染中很少出现，但对疾病进展起保护作用，并且针对Tat的疫苗可以增强cART的效果。事实上，在意大利和南非，对接受抑制性cART治疗的受试者进行Tat疫苗接种可促进免疫恢复，包括增加低免疫反应者的CD4 + T细胞，甚至在cART治疗六年之后，当CD4 + T细胞增加和病毒前体DNA衰减均达到平台期时，病毒前体DNA仍会减少。值得注意的是，抗Tat抗体对Tat介导的Env进入树突状细胞的中和作用可预测DNA衰减，这些抗体具有跨亚型结合和中和作用。抗Tat细胞免疫也有助于DNA衰减。基于这些数据，我们提出Tat治疗性疫苗是一种由发病机制驱动的干预措施，可有效增强cART的效果，并可能导致功能性治愈，也为预防和病毒根除策略提供了新的视角和机会。
