Muniz Cláudia P, Soares Marcelo A, Santos André F
Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Programa de Genética, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
J Antimicrob Chemother. 2014 Oct;69(10):2741-5. doi: 10.1093/jac/dku214. Epub 2014 Jun 19.
Interpretation of drug resistance mutation (DRM) has been based solely on HIV-1 subtype B. Reverse transcriptase (RT) C-terminal domains have been disregarded in resistance interpretation, as their clinical relevance is still controversial. We determined the emergence of DRM in RT C-terminal domains of different HIV-1 subtypes, the genetic barrier for the acquisition of these DRM and their temporal appearance with 'classical' RT inhibitor (RTI) mutations.
HIV-1 RT sequences were obtained from information from 6087 treatment-naive and 3795 RTI-treated patients deposited in the Stanford HIV Resistance Database, including all major subtypes. DRM emergence was evaluated for subtype B, and was correlated with the number of DRM in the polymerase domain. Genetic barrier was calculated for each DRM studied and in each subtype.
N348I, T369I and A360V were found at low prevalence in treatment-naive isolates of all subtypes. A371V was common to treatment-naive isolates. N348I was observed in all subtypes, while T369I was only selected in subtype C. A360V and T369V were selected by RTI treatment in several subtypes. A371V was selected in subtypes B and C, but is a signature in subtype A. RT C-terminal mutations were correlated with early drug resistance in subtype B. All subtypes have a low calculated genetic barrier towards C-terminal DRM acquisition, despite a few disparities having been observed.
C-terminal mutations were selected in all HIV-1 subtypes, while some represent subtype-specific signatures. The selection of C-terminal DRMs occurs early in RTI resistance failure in subtype B.
耐药性突变（DRM）的解读一直仅基于HIV-1 B亚型。逆转录酶（RT）的C末端结构域在耐药性解读中一直被忽视，因为其临床相关性仍存在争议。我们确定了不同HIV-1亚型RT C末端结构域中DRM的出现情况、获得这些DRM的遗传屏障以及它们与“经典”逆转录酶抑制剂（RTI）突变的出现时间。
从斯坦福HIV耐药数据库中获取的6087例未经治疗和3795例接受RTI治疗患者的信息中获得HIV-1 RT序列，包括所有主要亚型。评估了B亚型中DRM的出现情况，并将其与聚合酶结构域中DRM的数量相关联。计算了所研究的每个DRM在每种亚型中的遗传屏障。
在所有亚型未经治疗的分离株中，N348I、T369I和A360V的发生率较低。A371V在未经治疗的分离株中很常见。在所有亚型中均观察到N348I，而T369I仅在C亚型中被选择。在几种亚型中，RTI治疗选择了A360V和T369V。在B和C亚型中选择了A371V，但它是A亚型的特征。RT C末端突变与B亚型的早期耐药性相关。尽管观察到一些差异，但所有亚型对获得C末端DRM的遗传屏障都较低。
在所有HIV-1亚型中均选择了C末端突变，而有些代表亚型特异性特征。在B亚型中，RTI耐药失败早期就出现了C末端DRM的选择。
