Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 8091 Zurich, Switzerland.
J Infect Dis. 2010 Apr 1;201(7):1054-62. doi: 10.1086/651168.
The connection domain mutation N348I confers resistance to zidovudine (AZT) and is associated with the lamivudine (3TC) mutation M184V. We explored the biochemical and virological influence of N348I in the context of M184V.
Genotypic resistance data for patients receiving monotherapy or dual therapy with AZT, lamivudine (3TC), or AZT/3TC were analyzed. Rates of N348I emergence were compared between treatment groups. Mutant reverse transcriptases (RTs) containing M184V and/or N348I were generated to study enzymatic and virological properties.
We included 50 AZT-treated, 11 3TC-treated, and 10 AZT/3TC-treated patients. N348I was observed in 3 (6%), 0, and 4 (40%) of these patients, respectively. The rate of N348I emergence was increased by 5-fold in the AZT/3TC group (11.7 instances [95% confidence interval {CI}, 3.2-30.1 instances] per 100 person-years of receipt of AZT), compared with the rate noted for the AZT group (2.3 instances [95% CI, 0.4-6.8 instances] per 100 person-years of receipt of AZT; P = .04). Biochemical data show that N348I can partially compensate for the diminution in processive DNA synthesis and the reduction in AZT excision associated with M184V. Furthermore, virological analyses demonstrate that N348I confers low-level resistance to AZT and partly restores the reduced RT activity of the M184V variant.
In vivo selection of N348I is driven by AZT and is further facilitated when 3TC is coadministered. Compensatory interactions between N348I and M184V help to explain these findings.
连接域突变 N348I 赋予对齐多夫定（AZT）的耐药性，并与拉米夫定（3TC）突变 M184V 相关。我们探讨了 N348I 在 M184V 背景下的生化和病毒学影响。
分析了接受 AZT、拉米夫定（3TC）或 AZT/3TC 单药或联合治疗的患者的基因型耐药数据。比较了治疗组中 N348I 出现的比率。生成含有 M184V 和/或 N348I 的突变逆转录酶（RT）以研究酶学和病毒学特性。
我们纳入了 50 例接受 AZT 治疗、11 例接受 3TC 治疗和 10 例接受 AZT/3TC 治疗的患者。分别在 3（6%）、0 和 4（40%）例患者中观察到 N348I。与 AZT 组相比，AZT/3TC 组 N348I 的出现率增加了 5 倍（AZT 治疗每 100 人年出现 11.7 例[95%置信区间{CI}，3.2-30.1 例]），而 AZT 组的出现率为 2.3 例[95%CI，0.4-6.8 例]；每 100 人年 AZT 治疗的例数；P=.04）。生化数据表明，N348I 可部分补偿 M184V 相关的持续 DNA 合成减少和 AZT 切除减少。此外，病毒学分析表明，N348I 赋予 AZT 低水平耐药性，并部分恢复了 M184V 变异体降低的 RT 活性。
N348I 的体内选择由 AZT 驱动，当 3TC 联合给药时，选择进一步促进。N348I 和 M184V 之间的补偿相互作用有助于解释这些发现。
