Efficacy of Antiretroviral Agents against Murine Replication-Competent Retrovirus Infection in Human Cells

Retroviral vectors for gene therapy are designed to minimize the occurrence of replication-competent retrovirus (RCR); nonetheless, it is possible that a vector-derived RCR could establish an infection in a patient. Since the efficacy of antiretroviral agents can be impacted by interactions between virus, host cell, and drug, five commonly used antiretroviral drugs were evaluated for their abilities to inhibit the replication of a murine leukemia virus (MLV)-derived RCR in human cells. The results obtained indicate that the combination of nucleoside analogs zidovudine and dideoxyinosine with the protease inhibitor indinavir effectively inhibits MLV-derived RCR replication in three human cell lines. In addition, MLV-derived RCR was found to be inherently resistant to the nucleoside analogs lamivudine and stavudine, suggesting that mutations conferring resistance to nucleoside analogs in human immunodeficiency virus type 1 have the same effect even in an alternative viral backbone.

用于基因治疗的逆转录病毒载体在研发阶段即会尽可能降低复制型逆转录病毒（replication-competent retrovirus, RCR）的生成概率；然而，载体衍生的复制型逆转录病毒仍有可能在患者体内建立感染。鉴于抗逆转录病毒药物的疗效会受到病毒、宿主细胞与药物三者间相互作用的影响，本研究评估了5种常用抗逆转录病毒药物对人源细胞中鼠白血病病毒（murine leukemia virus, MLV）衍生的复制型逆转录病毒的复制抑制能力。实验结果表明，核苷类似物齐多夫定与双脱氧肌苷联合蛋白酶抑制剂茚地那韦，可在3种人源细胞系中有效抑制鼠白血病病毒衍生的复制型逆转录病毒的复制。此外，研究发现鼠白血病病毒衍生的复制型逆转录病毒对核苷类似物拉米夫定与司他夫定具有固有耐药性，这提示1型人类免疫缺陷病毒（human immunodeficiency virus type 1）中赋予核苷类似物耐药性的突变，在其他病毒骨架中同样可产生相同的耐药效果。