RNA 糖苷酶和其他试剂靶向 Tat 以抑制 HIV-1 转录。

RNA glycosidase and other agents target Tat to inhibit HIV-1 transcription.

机构信息

QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, 4029 Brisbane, Queensland, Australia

QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, 4029 Brisbane, Queensland, Australia.

出版信息

Biochem J. 2018 Mar 20;475(6):1059-1062. doi: 10.1042/BCJ20170669.

DOI:10.1042/BCJ20170669

PMID:29559581

Abstract

The HIV-1 gene encodes a small 86-104 amino acid protein depending on the HIV-1 strain. Tat is essential for HIV-1 replication through interactions with numerous cellular transcription factors. The interaction between Tat and P-TEFb, which is a cellular protein complex composed of cyclin T1 and CDK9, delivers P-TEFb to the newly transcribed viral mRNAs where phosphorylation of RNA polymerase II by CDK9 leads to highly efficient mRNA transcription. It has long been recognized that Tat is a potential anti-HIV-1 target and possibly a viral Achilles' heel. However, specifically targeting Tat without affecting normal host cell functions has been challenging. Means to inactivate Tat have been reported that includes small compounds, transdominant negative Tat proteins, and by plant-derived antivirals. Investigations of these agents have reported encouraging outcomes that inform and may hopefully affect strategies for a functional HIV-1 cure.

摘要

HIV-1 基因编码一个小的 86-104 个氨基酸的蛋白质，具体取决于 HIV-1 株。Tat 对 HIV-1 复制是必需的，它通过与许多细胞转录因子相互作用来实现。Tat 与 P-TEFb 的相互作用，P-TEFb 是一种由 cyclin T1 和 CDK9 组成的细胞蛋白复合物，将 P-TEFb 递送到新转录的病毒 mRNA 上，CDK9 对 RNA 聚合酶 II 的磷酸化导致高效的 mRNA 转录。长期以来，人们一直认为 Tat 是一种潜在的抗 HIV-1 靶点，可能是病毒的致命弱点。然而，特异性地靶向 Tat 而不影响正常的宿主细胞功能一直具有挑战性。已报道了几种使 Tat 失活的方法，包括小分子、显性负 Tat 蛋白和植物来源的抗病毒药物。对这些药物的研究报告了令人鼓舞的结果，这些结果为功能性 HIV-1 治愈策略提供了信息，并可能产生影响。