Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N 15th St, Philadelphia, PA, 19102, USA.
Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, USA.
Med Microbiol Immunol. 2019 Apr;208(2):131-169. doi: 10.1007/s00430-019-00583-z. Epub 2019 Mar 5.
Human immunodeficiency virus type 1 (HIV-1) encodes a transactivator of transcription (Tat) protein, which has several functions that promote viral replication, pathogenesis, and disease. Amino acid variation within Tat has been observed to alter the functional properties of Tat and, depending on the HIV-1 subtype, may produce Tat phenotypes differing from viruses' representative of each subtype and commonly used in in vivo and in vitro experimentation. The molecular properties of Tat allow for distinctive functional activities to be determined such as the subcellular localization and other intracellular and extracellular functional aspects of this important viral protein influenced by variation within the Tat sequence. Once Tat has been transported into the nucleus and becomes engaged in transactivation of the long terminal repeat (LTR), various Tat variants may differ in their capacity to activate viral transcription. Post-translational modification patterns based on these amino acid variations may alter interactions between Tat and host factors, which may positively or negatively affect this process. In addition, the ability of HIV-1 to utilize or not utilize the transactivation response (TAR) element within the LTR, based on genetic variation and cellular phenotype, adds a layer of complexity to the processes that govern Tat-mediated proviral DNA-driven transcription and replication. In contrast, cytoplasmic or extracellular localization of Tat may cause pathogenic effects in the form of altered cell activation, apoptosis, or neurotoxicity. Tat variants have been shown to differentially induce these processes, which may have implications for long-term HIV-1-infected patient care in the antiretroviral therapy era. Future studies concerning genetic variation of Tat with respect to function should focus on variants derived from HIV-1-infected individuals to efficiently guide Tat-targeted therapies and elucidate mechanisms of pathogenesis within the global patient population.
人类免疫缺陷病毒 1 型（HIV-1）编码一种转录激活蛋白（Tat），它具有多种促进病毒复制、发病机制和疾病的功能。Tat 内的氨基酸变异已被观察到改变 Tat 的功能特性，并且取决于 HIV-1 亚型，可能产生与每种亚型的代表病毒不同的 Tat 表型，并且常用于体内和体外实验。Tat 的分子特性允许确定独特的功能活性，例如这种重要病毒蛋白的亚细胞定位和其他细胞内和细胞外功能方面，这些功能方面受 Tat 序列内的变异影响。一旦 Tat 被运送到细胞核并参与长末端重复序列（LTR）的转录激活，各种 Tat 变体在激活病毒转录的能力上可能有所不同。基于这些氨基酸变异的翻译后修饰模式可能改变 Tat 与宿主因子之间的相互作用，这可能对该过程产生积极或消极的影响。此外，HIV-1 基于遗传变异和细胞表型利用或不利用 LTR 内的转录激活反应（TAR）元件的能力增加了控制 Tat 介导的前病毒 DNA 驱动转录和复制的过程的复杂性。相比之下，Tat 的细胞质或细胞外定位可能以改变细胞激活、细胞凋亡或神经毒性的形式引起发病机制效应。已经表明 Tat 变体可差异诱导这些过程，这可能对抗逆转录病毒治疗时代的长期 HIV-1 感染患者护理产生影响。关于 Tat 功能的遗传变异的未来研究应集中在来自 HIV-1 感染个体的变体上，以有效地指导针对 Tat 的治疗，并阐明全球患者群体中的发病机制机制。
