HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture
HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture
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DOI：
10.1097/01.aids.0000232228.88511.0b
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发表时间：
2006-06-12
期刊：
影响因子：
3.8
通讯作者：
Wainberg, Mark A.
中科院分区：
文献类型：
--
作者：
Brenner, Bluma G.;Oliveira, Maureen;Wainberg, Mark A.
背景：HIV-1 亚型和循环重组形式 (CRF) 之间的基因型多样性可能导致不同的耐药途径。本研究评估了替诺福韦培养物耐药性发展中与亚型相关的差异。方法：基因分型确定了亚型之间的核苷酸多样性。选择代表性亚型 B、C、CRF1_AE、CRF2_AG、G 和 HIV-2 分离株，用于细胞培养中对替诺福韦、拉米夫定和去羟肌苷的耐药性。表型测定确定了逆转录酶 (RT) 中 K65R 取代对药物敏感性的影响。结果：C 亚型分离株在 RT 密码子 64 (AAG -> AAA)、65 (AAA -> AAG) 和 66 (AAA -> AAG) 中显示出独特的多态性，而其他亚型则不存在。在四个 C 亚型选择中，第 12 周时替诺福韦出现了 K65R 突变 (AAG -> AGG)。相比之下，四个B亚型（> 34-74周）、CRF2_AG和G（> 30-33周）各一个以及三个HIV-2（> 27-28周）选择中没有出现替诺福韦耐药性。在使用替诺福韦的两次 CRFIAE 选择中，K65R 在 55 周和 73 周后出现。相比之下，在拉米夫定压力下出现 M184V 的时间（第 8-14 周）在亚型之间没有差异。选择性去羟肌苷压力导致 38 周后，四种 C 亚型选择中的两种出现 M184V 和 L74V。 C 亚型和其他亚型（AGG 和 AGA）中的 K65R 转变对替诺福韦产生相似的 6.5-10 倍耐药性，对阿巴卡韦、拉米夫定和去羟肌苷分别具有 5 至 25 倍的交叉耐药性，同时不影响齐多夫定的敏感性。 结论：在 C 亚型感染中，需要仔细监测基于替诺福韦的治疗方案，以便选择可能的治疗方案。 K65R。 (c) 2006 年利平科特·威廉姆斯和威尔金斯。
Background: Genotypic diversity among HIV-1 subtypes and circulating recombinant forms (CRF) may lead to distinct pathways to drug resistance. This study evaluated subtype-related differences in the development of resistance in culture to tenofovir.Methods: Genotyping determined nucleotide diversity among subtypes. Representative subtype B, C, CRF1_AE, CRF2_AG, G, and HIV-2 isolates were selected for resistance to tenofovir, lamivudine and didanosine in cell culture. Phenotypic assays determined the effects of the K65R substitution in reverse transcriptase (RT) on drug susceptibility.Results: Subtype C isolates show unique polymorphisms in RT codons 64 (AAG -> AAA), 65 (AAA -> AAG), and 66 (AAA -> AAG), absent in other subtypes. The K65R mutation (AAG -> AGG) arose with tenofovir by week 12 in four subtype C selections. In contrast, no tenofovir resistance arose in four subtype B (> 34-74 weeks), one each of CRF2_AG and G (> 30-33 weeks), and three HIV-2 (> 27-28 weeks) selections. K65R appeared after 55 and 73 weeks in two CRFIAE selections with tenofovir. In contrast, times to the appearance of M184V with lamivudine pressure (weeks 8-14) did not vary among subtypes. Selective didanosine pressure resulted in the appearance of M184V and L74V after 38 weeks in two of four subtype C selections. The K65R transitions in subtype C and other subtypes (AGG and AGA) conferred similar 6.5-10-fold resistance to tenofovir and five to 25-fold crossresistance to each of abacavir, lamivudine, and didanosine, while not affecting zidovudine susceptibility.Conclusion: Tenofovir -based regimens will need to be carefully monitored in subtype C infections for the possible selection of K65R. (c) 2006 Lippincott Williams & Wilkins.