Department of Microbiology, University of Hong Kong, Hong Kong SAR, Guangzhou CDC, Guangzhou, China.
PLoS One. 2012;7(9):e44333. doi: 10.1371/journal.pone.0044333. Epub 2012 Sep 12.
Since the antiretroviral therapy (ART) was introduced to patients infected by human immunodeficiency virus (HIV), the HIV related mortality and morbidity have been significantly reduced. The major obstacle for long-term successful anti-HIV treatment is the emergence of drug resistant mutants. Current data of drug resistance was mainly obtained on HIV-1 subtype B but rarely on non-B virus, even more rare with newly emerged circulating recombinant forms (CRFs). The lack of such data limits the rational management of ART for the increasing number of patients infected by non-subtype B virus. In this study, a HIV-1 CRF07_BC strain CNGZD was isolated from a HIV patient and its genome was sequenced and deposited in GenBank (JQ423923). Potential drug resistant mutants of this CRF07_BC virus strain were selected in PBMCs cultures in the presence of Nevirapine (NVP), which is the most frequently used antiretroviral drug in China. Four combination profiles of mutations were identified in the NVP-selected mutants, which were initiated with A98G, V108I, Y181C and I135T/I382L and followed by more than two other mutations at the end of the selections, respectively. A total of seven previously reported mutations (A98G, V106M, V108I, I135T, Y181C, V189I, K238N) and seven novel mutations (P4H, T48I, I178M, V314A, I382L/V, T386A) in the reverse transcriptase gene were found in these NVP-selected mutants. Phenotypic analysis in the NVP-selected mutants showed that all the mutations, except P4H, contribute to NVP resistance. Among them, V106M and Y181C reduce NVP susceptibility for more than 20-fold, while the other mutations cause less than 20 folds drug resistance. Although the information obtained in this in vitro selection study may not fully cover resistant mutations which will actually occur in patients, it has still provided useful information for rational management of ART in patients infected with HIV CRF_BC subtype.
自人类免疫缺陷病毒（HIV）感染者接受抗逆转录病毒治疗（ART）以来，HIV 相关的死亡率和发病率已显著降低。长期成功抗 HIV 治疗的主要障碍是耐药突变体的出现。目前的耐药数据主要来自 HIV-1 亚型 B，但很少涉及非 B 型病毒，甚至新出现的重组形式（CRF）更为罕见。缺乏此类数据限制了对越来越多感染非 B 型病毒患者的 ART 的合理管理。在这项研究中，从一名 HIV 患者中分离出一株 HIV-1 CRF07_BC 株 CNGZD，并将其基因组序列提交至 GenBank（JQ423923）。在含有奈韦拉平（NVP）的 PBMCs 培养物中选择了这种 CRF07_BC 病毒株的潜在耐药突变体，NVP 是中国最常用的抗逆转录病毒药物。在 NVP 选择的突变体中，鉴定出四种组合的突变谱，分别由 A98G、V108I、Y181C 和 I135T/I382L 起始，并在选择结束时分别有两个以上的其他突变。在这些 NVP 选择的突变体中发现了总共七个先前报道的突变（A98G、V106M、V108I、I135T、Y181C、V189I、K238N）和七个新的突变（P4H、T48I、I178M、V314A、I382L/V、T386A）。在 NVP 选择的突变体中的表型分析表明，除 P4H 外，所有突变均导致 NVP 耐药。其中，V106M 和 Y181C 使 NVP 敏感性降低 20 多倍，而其他突变导致不到 20 倍的耐药性。尽管在这项体外选择研究中获得的信息可能不能完全涵盖实际发生在患者中的耐药突变，但它仍然为感染 HIV CRF_BC 亚型的患者的 ART 合理管理提供了有用的信息。
