de la Carrière L C, Paulous S, Clavel F, Mammano F
Unité d'Oncologie Virale, Institut Pasteur and Laboratoire de Recherche Antivirale, Hôpital Bichat-Claude Bernard, Paris, France.
J Virol. 1999 Apr;73(4):3455-9. doi: 10.1128/JVI.73.4.3455-3459.1999.
Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease inhibitors often display a reduced replicative capacity as a result of an impairment of protease function. Such fitness-impaired viruses display Gag precursor maturation defects. Here, we report that some protease inhibitor-resistant viruses also display abnormalities in the processing of reverse transcriptase (RT) by the protease. In three recombinant viruses carrying resistant protease sequences from patient plasma, we observed a marked decrease in the amount of mature RT subunits and of particle-associated RT activity compared to their parental pretherapy counterparts. We investigated the possibility that a decrease in the amount of particle-associated mature RT could affect the sensitivity of the corresponding virus to RT inhibitors. We observed a twofold increase of sensitivity to zidovudine (AZT) when a virus which carried AZT mutations was processed by a resistant protease. Interestingly, the presence of AZT-resistance mutations partially rescued the replication defect associated with the mutated protease. The interplay between resistance to protease inhibitors and to RT inhibitors described here may be relevant to the therapeutic control of HIV-1 infection.
1型人类免疫缺陷病毒（HIV-1）对蛋白酶抑制剂耐药的变体，由于蛋白酶功能受损，通常表现出复制能力降低。这种适应性受损的病毒表现出Gag前体成熟缺陷。在此，我们报告一些对蛋白酶抑制剂耐药的病毒在蛋白酶对逆转录酶（RT）的加工过程中也表现出异常。在三种携带来自患者血浆耐药蛋白酶序列的重组病毒中，我们观察到与它们的治疗前亲代病毒相比，成熟RT亚基的量以及颗粒相关RT活性显著降低。我们研究了颗粒相关成熟RT量的减少是否会影响相应病毒对RT抑制剂敏感性的可能性。当携带齐多夫定（AZT）突变的病毒由耐药蛋白酶加工时，我们观察到其对AZT的敏感性增加了两倍。有趣的是，AZT耐药突变的存在部分挽救了与突变蛋白酶相关的复制缺陷。这里描述的对蛋白酶抑制剂和RT抑制剂的耐药之间的相互作用可能与HIV-1感染的治疗控制有关。
