Shadrina O A, Zatsepin T S, Agapkina Yu Yu, Isaguliants M G, Gottikh M B
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Leninskie gory, Moscow, 119991, Russia.
Belozersky Institute of Physical-Chemical Biology, Lomonosov Moscow State University, Leninskie gory, Moscow, Russia; 119991 ; Chemistry Department, Lomonosov Moscow State University, Leninskie gory, Moscow, 119991, Russia.
Acta Naturae. 2015 Jan-Mar;7(1):78-86.
Integration of human immunodeficiency virus (HIV-1) DNA into the genome of an infected cell is one of the key steps in the viral replication cycle. The viral enzyme integrase (IN), which catalyzes the integration, is an attractive target for the development of new antiviral drugs. However, the HIV-1 therapy often results in the IN gene mutations inducing viral resistance to integration inhibitors. To assess the impact of drug resistance mutations on the activity of IN of HIV-1 subtype A strain FSU-A, which is dominant in Russia, variants of the consensus IN of this subtype containing the primary resistance mutations G118R and Q148K and secondary compensatory substitutions E138K and G140S were prepared and characterized. Comparative study of these enzymes with the corresponding mutants of IN of HIV-1 subtype B strains HXB-2 was performed. The mutation Q148K almost equally reduced the activity of integrases of both subtypes. Its negative effect was partially compensated by the secondary mutations E138K and G140S. Primary substitution G118R had different influence on the activity of proteins of the subtypes A and B, and the compensatory effect of the secondary substitution E138K also depended on the viral subtype. Comparison of the mutants resistance to the known strand transfer inhibitors raltegravir and elvitegravir, and a new inhibitor XZ-259 (a dihydro-1H-isoindol derivative), showed that integrases of both subtypes with the Q148K mutation were insensitive to raltegravir and elvitegravir but were effectively inhibited by XZ-259. The substitution G118R slightly reduced the efficiency of IN inhibition by raltegravir and elvitegravir and caused no resistance to XZ_259.
人类免疫缺陷病毒（HIV-1）DNA整合到受感染细胞的基因组中是病毒复制周期的关键步骤之一。催化整合的病毒酶整合酶（IN）是开发新型抗病毒药物的一个有吸引力的靶点。然而，HIV-1治疗常常导致IN基因突变，从而使病毒对整合抑制剂产生抗性。为了评估耐药性突变对在俄罗斯占主导地位的HIV-1 A亚型FSU-A株IN活性的影响，制备并表征了该亚型共有IN的变体，这些变体包含主要耐药突变G118R和Q148K以及次要补偿性替代E138K和G140S。对这些酶与HIV-1 B亚型菌株HXB-2的相应IN突变体进行了比较研究。突变Q148K几乎同等程度地降低了两种亚型整合酶的活性。其负面影响被次要突变E138K和G140S部分补偿。主要替代G118R对A和B亚型蛋白质的活性有不同影响，次要替代E138K的补偿作用也取决于病毒亚型。对突变体对已知链转移抑制剂拉替拉韦和埃替拉韦以及新型抑制剂XZ-259（一种二氢-1H-异吲哚衍生物）的耐药性比较表明，具有Q-148K突变的两种亚型的整合酶对拉替拉韦和埃替拉韦不敏感，但被XZ-259有效抑制。替代G118R略微降低了拉替拉韦和埃替拉韦对IN的抑制效率，并且对XZ-259没有抗性。
