State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention (China-CDC), Beijing 102206, China.
J Antimicrob Chemother. 2013 Nov;68(11):2521-4. doi: 10.1093/jac/dkt228. Epub 2013 Jun 20.
To understand the effect of HIV-1 drug resistance mutations in the context of antiretroviral therapy (ART), we compared the prevalence of protease (PR) and reverse transcriptase (RT) mutations in HIV-1 CRF07_BC sequences from blood samples of treatment-naive and ART-treated patients.
Mutation covariation in the RT and PR of HIV-1 CRF07_BC viruses from 542 treatment-naive patients and 261 patients treated with lamivudine/zidovudine/nevirapine or lamivudine/zidovudine/efavirenz was analysed. Stratified networks were used to display the mutation covariation.
Based on the comparison between treatment-naive and ART-treated patients, three types of featured mutations for RT and PR were initially identified: treatment-associated mutations, treatment-agonistic mutations and overlapping polymorphisms. Twelve significant covariation pairs were found between five treatment-associated mutations (K103N, M184V, Q197K, G190A and Y181C) and nine overlapping polymorphisms (A36E, D39N, Y121H, D123E, R135I, T200A, R277K, L283I and D291E). Meanwhile, three covariation pairs between three treatment-associated mutations (I132L and M184V for RT and I15V for PR) and three overlapping polymorphisms (L10I, L36M and A71V) for PR were also detected. Finally, the overlapping polymorphisms for RT and PR were both found to have significant correlations with treatment-associated mutations, indicating a possible association between polymorphisms and drug resistance. When compared with HIV-1 subtype B under the same regimens as CRF07_BC, the mutation covariations of CRF07_BC showed a distinct pattern of RT and PR mutation covariation.
The role of polymorphisms in the development of drug resistance has been widely reported. Here, we found a significant correlation between overlapping polymorphisms for RT and PR and treatment-associated mutations, indicating that polymorphisms exert a global influence on treatment-associated mutations. Polymorphism mutations might therefore be considered before initiating ART to improve the efficacy of drug combinations.
为了了解 HIV-1 耐药突变在抗逆转录病毒治疗（ART）中的作用，我们比较了未经治疗和接受 ART 治疗的患者血液样本中 HIV-1 CRF07_BC 序列中蛋白酶（PR）和逆转录酶（RT）突变的流行率。
对 542 例未经治疗的患者和 261 例接受拉米夫定/齐多夫定/奈韦拉平或拉米夫定/齐多夫定/依非韦伦治疗的患者的 HIV-1 CRF07_BC 病毒的 RT 和 PR 中的突变共变进行了分析。分层网络用于显示突变共变。
根据未经治疗和接受 ART 治疗的患者之间的比较，最初确定了 RT 和 PR 的三种特征性突变类型：治疗相关突变、治疗促进突变和重叠多态性。在五个治疗相关突变（K103N、M184V、Q197K、G190A 和 Y181C）和九个重叠多态性（A36E、D39N、Y121H、D123E、R135I、T200A、R277K、L283I 和 D291E）之间发现了 12 个显著的共变对。同时，还检测到三个治疗相关突变（RT 的 I132L 和 M184V 以及 PR 的 I15V）和三个重叠多态性（PR 的 L10I、L36M 和 A71V）之间的三个共变对。最后，发现 RT 和 PR 的重叠多态性与治疗相关突变均具有显著相关性，表明多态性与耐药性之间可能存在关联。当与 CRF07_BC 相同方案下的 HIV-1 亚型 B 进行比较时，CRF07_BC 的 RT 和 PR 突变共变显示出明显不同的模式。
多态性在耐药性发展中的作用已被广泛报道。在这里，我们发现 RT 和 PR 的重叠多态性与治疗相关突变之间存在显著相关性，表明多态性对治疗相关突变具有全局影响。因此，在开始 ART 之前，可能需要考虑多态性突变，以提高药物组合的疗效。
