HIV-1 C亚型病毒在细胞培养中对替诺福韦迅速产生K65R耐药性。

HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture.

作者信息

Brenner Bluma G, Oliveira Maureen, Doualla-Bell Florence, Moisi Daniela D, Ntemgwa Michel, Frankel Fernando, Essex Max, Wainberg Mark A

机构信息

McGill University AIDS Centre, Jewish General Hospital, 3755 Côte Ste Catherine Road, Montreal, Quebec, Canada.

出版信息

AIDS. 2006 Jun 12;20(9):F9-13. doi: 10.1097/01.aids.0000232228.88511.0b.

DOI:10.1097/01.aids.0000232228.88511.0b

PMID:16816549

Abstract

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 CRF1_AE 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 cross-resistance 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.

摘要

背景

HIV-1亚型和循环重组型（CRF）之间的基因多样性可能导致不同的耐药途径。本研究评估了在细胞培养中对替诺福韦耐药性发展的亚型相关差异。

方法

基因分型确定亚型间的核苷酸多样性。选择代表性的B亚型、C亚型、CRF1_AE、CRF2_AG、G亚型和HIV-2分离株，在细胞培养中检测其对替诺福韦、拉米夫定和去羟肌苷的耐药性。表型分析确定逆转录酶（RT）中K65R替换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）处显示独特的多态性，其他亚型不存在。在四个C亚型选择中，到第12周时，K65R突变（AAG→AGG）与替诺福韦一起出现。相比之下，在四个B亚型（>34 - 74周）、CRF2_AG和G亚型各一个（>30 - 33周）以及三个HIV-2（>27 - 28周）选择中，未出现替诺福韦耐药。在两个接受替诺福韦的CRF1_AE选择中，K65R分别在55周和73周后出现。相比之下，在拉米夫定压力下M184V出现的时间（8 - 14周）在各亚型间没有差异。在四个C亚型选择中的两个中，选择性的去羟肌苷压力导致38周后出现M184V和L74V。C亚型和其他亚型中的K65R转换（AGG和AGA）对替诺福韦产生相似的6.5 - 10倍耐药，对阿巴卡韦、拉米夫定和去羟肌苷各产生5至25倍的交叉耐药，同时不影响齐多夫定的敏感性。