Institut de Recerca de la SIDA--IrsiCaixa, Spain.
J Infect Dis. 2011 Sep 1;204(5):741-52. doi: 10.1093/infdis/jir385.
The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain.
The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT.
Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4; 95% confidence interval [CI], 2.0-54.7), but it did not affect efavirenz outcome the same way (RH = 0.5; 95% CI, 0.1-2.2) (P value for interaction = .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA.
The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART.
HIV-1 逆转录酶（RT）连接亚区和核糖核酸酶（RNase）H 结构域突变的临床相关性尚不确定。
根据 HIV-1 RT 连接亚区和 RNase H 结构域中预先存在的替代物，评估 1997 年 7 月后在 EuroSIDA 研究中开始使用非核苷类 RT 抑制剂（NNRTI）的 NNRTI 初治患者接受 NNRTI 基于抗逆转录病毒治疗（ART）时发生病毒学失败的风险。通过检测单点定向突变体和患者来源的重组病毒的体外 NNRTI 敏感性，进一步研究 A376S 与病毒学失败之间的关联。酶促测定还确定了 A376S 对奈韦拉平与 HIV-1 RT 模板-引物结合的影响。
287 例患者中有 142 例（49%）发生病毒学失败：77 例接受奈韦拉平（67%），65 例接受依非韦伦（38%）（P <.001）。预先存在的 A376S 与奈韦拉平病毒学失败的风险增加相关（相对危险[RH] = 10.4；95%置信区间[CI]，2.0-54.7），但对依非韦伦的结果没有同样的影响（RH = 0.5；95% CI，0.1-2.2）（P 值交互作用=.013）。A376S 在体外赋予奈韦拉平选择性低水平耐药性，并导致对双链 DNA 的亲和力增加。
HIV-1 RT 连接亚区的 A376S 取代导致奈韦拉平选择性耐药，并增加了基于奈韦拉平的 ART 发生病毒学失败的风险。
