National HIV/AIDS Research Center, Istituto Superiore di Sanità, 00161 Rome, Italy.
Int J Mol Sci. 2024 Jan 30;25(3):1704. doi: 10.3390/ijms25031704.
Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV replication and spreading. At this stage, most of the Tat protein exits infected cells, accumulates in the extracellular matrix and exerts profound effects on both the virus and neighbor cells, mostly of the innate and adaptive immune systems. Through these effects, extracellular Tat contributes to the acquisition of infection, spreading and progression to AIDS in untreated patients, or to non-AIDS co-morbidities in ART-treated individuals, who experience inflammation and immune activation despite virus suppression. Here, we review the role of extracellular Tat in both the virus life cycle and on cells of the innate and adaptive immune system, and we provide epidemiological and experimental evidence of the importance of targeting Tat to block residual HIV expression and replication. Finally, we briefly review vaccine studies showing that a therapeutic Tat vaccine intensifies ART, while its inclusion in a preventative vaccine may blunt escape from neutralizing antibodies and block early events in HIV acquisition.
每次病毒开始新一轮的表达/复制，即使在有效的抗逆转录病毒治疗（ART）下，转录激活蛋白 Tat 也是最早产生的 HIV-1 蛋白之一，因为它是 HIV 复制和传播所必需的。在这个阶段，大多数 Tat 蛋白从感染细胞中逸出，积累在细胞外基质中，并对病毒和邻近细胞产生深远的影响，主要是先天和适应性免疫系统。通过这些作用，细胞外 Tat 有助于未经治疗的患者获得感染、传播和进展为艾滋病，或有助于接受 ART 治疗的个体发生非艾滋病合并症，尽管病毒得到抑制，但这些个体仍会经历炎症和免疫激活。在这里，我们回顾了细胞外 Tat 在病毒生命周期和先天及适应性免疫系统细胞中的作用，并提供了针对 Tat 进行靶向以阻断残留 HIV 表达和复制的重要性的流行病学和实验证据。最后，我们简要回顾了疫苗研究，表明治疗性 Tat 疫苗可增强 ART，而将其纳入预防性疫苗中可能会削弱对中和抗体的逃逸，并阻止 HIV 获得的早期事件。
