Hu Zixin, Giguel Françoise, Hatano Hiroyu, Reid Patrick, Lu Jing, Kuritzkes Daniel R
Section of Retroviral Therapeutics, Brigham and Women's Hospital, 65 Landsdowne Street, Cambridge, MA 02139, USA.
J Virol. 2006 Jul;80(14):7020-7. doi: 10.1128/JVI.02747-05.
Resistance to zidovudine (ZDV) results from thymidine analog resistance mutations (TAMs) at human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) codons 41, 67, 70, 210, 215, and 219. Two mutations are possible at codon 215: Y or F. Whereas T215Y occurs alone or with M41L and L210W (TAM-1 pattern), T215F rarely occurs with these mutations or by itself; it is found instead with D67N, K70R, and K219Q (TAM-2 pattern). The L210W mutation most often occurs with M41L and T215Y and rarely occurs with the T215F or TAM-2 mutation. To explain these associations, TAMs were introduced into HIV-1(Hxb2) by site-directed mutagenesis and expressed in recombinant viruses. Viral replication kinetics, relative fitness, and infectivity were tested in the absence or presence of ZDV. Viruses carrying the 215Y mutation showed faster replication kinetics and greater relative fitness than did T215F mutants in the absence or presence of ZDV. In addition, T215Y mutants showed greater infectivity than did wild-type HIV-1 over a range of ZDV concentrations, but T215F mutants had only a modest advantage over the wild-type virus. Whereas introduction of L210W improved the relative fitness of an M41L/T215Y mutant in the presence of ZDV, introduction of this mutation into a D67N/K70R/K219Q background resulted in decreased relative fitness in the presence or absence of drug. By contrast, introduction of T215F into the D67N/K70R/K219Q background increased viral fitness in the presence of ZDV. These results help explain why T215Y but not T215F usually emerges as the first major TAM, as well as the clustering of L210W with TAM-1 mutations and T215F with TAM-2 mutations.
对齐多夫定（ZDV）的耐药性是由人类免疫缺陷病毒1型（HIV-1）逆转录酶（RT）密码子41、67、70、210、215和219处的胸苷类似物耐药性突变（TAM）引起的。密码子215处可能出现两种突变：Y或F。T215Y单独出现或与M41L和L210W一起出现（TAM-1模式），而T215F很少与这些突变一起出现或单独出现；相反，它与D67N、K70R和K219Q一起出现（TAM-2模式）。L210W突变最常与M41L和T215Y一起出现，很少与T215F或TAM-2突变一起出现。为了解释这些关联，通过定点诱变将TAM引入HIV-1（Hxb2）并在重组病毒中表达。在有或没有ZDV的情况下测试病毒复制动力学、相对适应性和感染性。在有或没有ZDV的情况下，携带215Y突变的病毒比T215F突变体显示出更快的复制动力学和更高的相对适应性。此外，在一系列ZDV浓度下，T215Y突变体比野生型HIV-1显示出更高的感染性，但T215F突变体仅比野生型病毒有适度优势。在有ZDV的情况下，引入L210W可提高M41L/T215Y突变体的相对适应性，但将此突变引入D67N/K70R/K219Q背景中，无论有无药物，相对适应性都会降低。相比之下，在有ZDV的情况下，将T215F引入D67N/K70R/K219Q背景中可提高病毒适应性。这些结果有助于解释为什么T215Y而非T215F通常会作为首个主要TAM出现，以及L210W与TAM-1突变以及T215F与TAM-2突变的聚集现象。
