Harrigan P Richard, Salim Mahboob, Stammers David K, Wynhoven Brian, Brumme Zabrina L, McKenna Paula, Larder Brendan, Kemp S D
BC Centre for Excellence in HIV/AIDS, 603-1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
J Virol. 2002 Jul;76(13):6836-40. doi: 10.1128/jvi.76.13.6836-6840.2002.
The Y318F substitution in the 3' region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has been linked to nonnucleoside RT inhibitor (NNRTI) resistance in vitro. A systematic search of a large phenotypic-genotypic database (Virco) linked the Y318F substitution with a >10-fold decrease in NNRTI susceptibility in >85% of clinically derived isolates. There was a significant association between Y318F and use of delavirdine (P = 10(-11)) and nevirapine (P = 10(-6)) but not efavirenz (P = 0.3). Site-directed HIV-1 Y318F mutants in an HXB2 background displayed 42-fold-decreased susceptibility to delavirdine but <3-fold-decreased susceptibility to nevirapine or efavirenz. Combinations of Y318F with K103N, Y181C, or both resulted in decreased efavirenz susceptibility of 43-, 3.3-, and 84-fold, respectively, as well as >100- and >60-fold decreases in delavirdine and nevirapine susceptibility, respectively. These results indicate the importance of the Y318F substitution in HIV-1 drug resistance.
人类免疫缺陷病毒1型（HIV-1）逆转录酶（RT）3'区域的Y318F替换在体外已与非核苷类逆转录酶抑制剂（NNRTI）耐药性相关联。对一个大型表型-基因型数据库（Virco）进行系统检索发现，在超过85%的临床分离株中，Y318F替换与NNRTI敏感性下降10倍以上有关。Y318F与地拉韦啶（P = 10^(-11)）和奈韦拉平（P = 10^(-6)）的使用之间存在显著关联，但与依非韦伦无关（P = 0.3）。在HXB2背景下的定点HIV-1 Y318F突变体对 地拉韦啶的敏感性降低了42倍，但对奈韦拉平或依非韦伦的敏感性降低不到3倍。Y318F与K103N、Y181C或两者的组合分别导致依非韦伦敏感性降低43倍、3.3倍和84倍，以及地拉韦啶和奈韦拉平敏感性分别降低100倍以上和60倍以上。这些结果表明Y318F替换在HIV-1耐药性中的重要性。
