4例接受抗病毒治疗的艾滋病患者HIV-1核苷类反转录酶抑制剂类耐药基因突变的选择动力学研究  

Research on the selective kinetics of HIV-1 nucleoside reverse transcriptase inhibitor drug resistanceassociated mutations among 4 AIDS patients receiving highly active antiretroviral therapy

作　　者：李珏[1] 焦丽燕[1] 李韩平[1] 李林[1] 刘永健[1] 庄道民[1] 刘思扬[1] 鲍作义[1] 李宏[2] 王哲[2] 李敬云[1] 

机构地区：[1]军事医学科学院微生物流行病研究所病原微生物生物安全国家重点实验室,北京100071 [2]河南省疾病预防控制中心

出　　处：《中华流行病学杂志》2008年第8期794-800,共7页Chinese Journal of Epidemiology

基　　金：国家“973”课题资助项目（2006CB504206）

摘　　要：目的阐明接受抗病毒治疗的艾滋病患者核苷类反转录酶抑制剂（nucleoside reverse transcriptase inhibitor，NRTI）类耐药基因突变分子进化特征。方法从中国中部农村某抗病毒治疗艾滋病病例研究队列中选择4例服药依从性较好，治疗初期为野生型毒株，在治疗过程中逐渐产生NRTI类耐药基因突变的患者为研究对象，对每位患者的4～5次随访血浆样本的反转录酶（RT）基因进行克隆测序分析，观察每个克隆的基因型耐药性特征。结果共检测855个克隆，平均每份血液样本47．5个±22．8个克隆，得到4例患者历次克隆序列中带各种NRTI类耐药基因突变的构成图谱：某些患者随治疗时间延长逐渐表现为典型的TAMs-1型突变模式，如L210W、T215Y、M41L突变，并且随治疗时间延长，优势种所携带的突变数目有累加趋势；某些患者表现为较明显的TAMs-2型突变，如K70R、D67N、K219Q等突变；其中，某些患者的克隆同时含有T215Y（TAMs-1型）和K70R、D67N（TAMs-2型）突变。结论总结出4例患者HIv-1NRTI类耐药基因突变的选择动力学特征。4例患者表现出不同的NRTI类耐药基因突变演变途径：TAMs-1型、TAMs-2型以及TAMs-1／TAMs-2融合型，该类突变表现出逐级累加的趋势，最先筛选出来的耐药突变往往能够成为最后的优势种。Objective To elucidate the molecular evolutional characteristics of HIV-I nucleoside reverse transcriptase inhibitor （NRTI） drug resistance-associated mutations in patients with AIDS receiving highly active antiretroviral therapy. Methods We selected 4 AIDS patients receiving highly active antiretroviral therapy （HAART） with good adherence under a HIV-1 drug resistance cohort from a rural region in central China. Those people carried susceptible virus at the beginning of treatment and gradually came to produce virus resistant to NRTIs during the process of antiretroviral therapy （ ART）. Reverse transcriptase（RT） genes from each patient＇s peripheral blood samples （from 3 to 33 months after withdrawal） were cloned and sequenced in succession. Resolts We sequenced a total number of 855 clones and obtained the HIV-1 NRTI drug resistance-assoclated mutations patterns of the 4 patients. Typical resistance mutations of thymidine analogue mutations （TAMs） pattern 1, such as L210V~, T215Y and M41L, were generated in patient ＇ A＇. TAMs pattern 2, including D67N, K70R and K219Q mutations, was discovered in patient ＇ B＇. Interestingly,in patient ＇C＇ , some clones comprising not only TAMs pattern 1 mutations（T215Y） but also TAMs pattern 2 mutations （K70R.D67N）. Conclusion The four patients show different pathways on HIV-1 NRTI drug resistance-associated mutations,including TAMs pattern 1, TAMs pattern 2 and the fusion pattern of TAMs-1 ＆ TAMs-2, We also noticed that the tendency of gradual accumulation was obvious and those mutations detected earlier tended to be the predominant strains.

关 键 词：核苷类反转录酶抑制剂 耐药基因突变 分子进化规律 

分 类 号：R51[医药卫生—内科学]