Halvas E K, Svarovskaia E S, Freed E O, Pathak V K
Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia 26506, USA.
J Virol. 2000 Jul;74(14):6669-74. doi: 10.1128/jvi.74.14.6669-6674.2000.
The antiretroviral nucleoside analog 2',3'-dideoxy-3'-thiacytidine (3TC) is a potent inhibitor of wild-type human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). A methionine-to-valine or methionine-to-isoleucine substitution at residue 184 in the HIV-1 YMDD motif, which is located at the RT active site, leads to a high level of resistance to 3TC. We sought to determine whether 3TC can inhibit the replication of wild-type murine leukemia virus (MLV), which contains V223 at the YVDD active site motif of the MLV RT, and of the V223M, V223I, V223A, and V223S mutant RTs. Surprisingly, the wild type and all four of the V223 mutants of MLV RT were highly resistant to 3TC. These results indicate that determinants outside the YVDD motif of MLV RT confer a high level of resistance to 3TC. Therefore, structural differences among similar RTs might result in widely divergent sensitivities to antiretroviral nucleoside analogs.
抗逆转录病毒核苷类似物2',3'-二脱氧-3'-硫代胞苷（3TC）是野生型人类免疫缺陷病毒1型（HIV-1）逆转录酶（RT）的有效抑制剂。位于RT活性位点的HIV-1 YMDD基序中第184位残基处的甲硫氨酸到缬氨酸或甲硫氨酸到异亮氨酸的取代会导致对3TC产生高度抗性。我们试图确定3TC是否能抑制野生型鼠白血病病毒（MLV）的复制，MLV在其RT的YVDD活性位点基序中含有V223，以及V223M、V223I、V223A和V223S突变体RT的复制。令人惊讶的是，MLV RT的野生型和所有四个V223突变体对3TC都具有高度抗性。这些结果表明，MLV RT的YVDD基序之外的决定因素赋予了对3TC的高度抗性。因此，相似RT之间的结构差异可能导致对抗逆转录病毒核苷类似物的敏感性差异很大。
