de la Fuente Cynthia, Maddukuri Anil, Kehn Kylene, Baylor Shanese Y, Deng Longwen, Pumfery Anne, Kashanchi Fatah
Department of Biochemistry and Molecular Biology, George Washington University, School of Medicine, Washington DC, 20037, USA.
Curr HIV Res. 2003 Apr;1(2):131-52. doi: 10.2174/1570162033485339.
Human immunodeficiency virus type 1 (HIV-1) can infect quiescent cells; however, viral production is restricted to actively proliferating cells. Recent evidence has indicated that HIV-1 viral proteins, Vpr and Tat, perturb the cell cycle to optimize HIV-1 replication. Vpr arrests the cell cycle at G2 by inactivating the cyclin B/cdk1 complex. Tat regulates the cell cycle by altering factors involved in proliferation and differentiation (i.e. the cdk inhibitor p21/waf1) and associating with cyclin/cdk complexes (i.e. cyclin E/cdk2, cyclin H/cdk7, and cyclin T/cdk9). These studies indicate the importance of host cellular factors, such as cyclin/cdk complexes, in regulating HIV-1 replication and therefore represent novel targets for antiviral therapeutics. Recently, the efficacy of pharmalogical cdk inhibitors (PCIs) in abrogating viral replication has been under development. To date there are 25-30 PCIs that have been synthesized against known cdks, several of which have been shown to inhibit HIV-1 and other AIDS-associated viruses in vitro and in vivo. Targeting these critical cyclin/cdk complexes needed for viral propagation may solve the problems inherent in current HAART therapy, including the emergence of drug-resistant viruses. Thus, PCIs have the potential to become novel therapeutic antiviral drugs that can inhibit HIV-1 transcription and opens the possibility of new avenues of treatment.
1型人类免疫缺陷病毒（HIV-1）能够感染静止细胞；然而，病毒产生仅限于活跃增殖的细胞。最近的证据表明，HIV-1病毒蛋白Vpr和Tat会扰乱细胞周期以优化HIV-1复制。Vpr通过使细胞周期蛋白B/细胞周期蛋白依赖性激酶1（cdk1）复合物失活，将细胞周期阻滞在G2期。Tat通过改变参与增殖和分化的因子（即细胞周期蛋白依赖性激酶抑制剂p21/waf1）并与细胞周期蛋白/细胞周期蛋白依赖性激酶复合物（即细胞周期蛋白E/cdk2、细胞周期蛋白H/cdk7和细胞周期蛋白T/cdk9）结合来调节细胞周期。这些研究表明宿主细胞因子，如细胞周期蛋白/细胞周期蛋白依赖性激酶复合物，在调节HIV-1复制中的重要性，因此代表了抗病毒治疗的新靶点。最近，药理学上的细胞周期蛋白依赖性激酶抑制剂（PCIs）在消除病毒复制方面的功效正在研发中。迄今为止，已经针对已知细胞周期蛋白依赖性激酶合成了25 - 30种PCIs，其中几种已被证明在体外和体内能够抑制HIV-1和其他与艾滋病相关的病毒。针对病毒繁殖所需的这些关键细胞周期蛋白/细胞周期蛋白依赖性激酶复合物可能解决当前高效抗逆转录病毒疗法（HAART）中固有的问题，包括耐药病毒的出现。因此，PCIs有潜力成为能够抑制HIV-1转录的新型治疗性抗病毒药物，并开辟新的治疗途径。
