Schinazi R F, Lloyd R M, Nguyen M H, Cannon D L, McMillan A, Ilksoy N, Chu C K, Liotta D C, Bazmi H Z, Mellors J W
Veterans Affairs Medical Center, Decatur, Georgia 30033.
Antimicrob Agents Chemother. 1993 Apr;37(4):875-81. doi: 10.1128/AAC.37.4.875.
The (-) enantiomers of 2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and 2',3'-dideoxy-3'-thiacytidine [(-)-BCH-189] were recently shown to inhibit selectively human immunodeficiency viruses (HIV) and hepatitis B virus in vitro. In the current study, the potential for HIV type 1 (HIV-1) resistance to these compounds was evaluated by serial passage of the virus in human peripheral blood mononuclear cells and MT-2 cells in the presence of increasing drug concentrations. Highly drug-resistant HIV-1 variants dominated the replicating virus population after two or more cycles of infection. The resistant variants were cross-resistant to (-)-FTC, (-)-BCH-189, and their (+) congeners but remained susceptible to 2',3'-dideoxycytidine, 3'-azido-3'-deoxythymidine, 3'-fluoro-3'-deoxythymidine, 2',3'-dideoxyinosine, phosphonoformate, the TIBO compound R82150, and the bis(heteroaryl)piperazine derivative U-87201E. Reverse transcriptase derived from drug-resistant viral particles was 15- to 50-fold less susceptible to the 5'-triphosphates of FTC and BCH-189 compared with enzyme from parental drug-susceptible virus. DNA sequence analysis of the reverse transcriptase gene amplified from resistant viruses consistently identified mutations at codon 184 from Met (ATG) to Val (GTG or GTA) or Ile (ATA). Sequence analysis of amplified reverse transcriptase from a patient who had received (-)-BCH-189 therapy for 4 months demonstrated a mixture of the Met-184-to-Val (GTG) mutation and the parental genotype, indicating that the Met-184 mutation can occur in vivo.
2',3'-二脱氧-5-氟-3'-硫代胞苷[(-)-FTC]和2',3'-二脱氧-3'-硫代胞苷[(-)-BCH-189]的(-)对映体最近显示在体外能选择性抑制人类免疫缺陷病毒（HIV）和乙型肝炎病毒。在当前研究中，通过在不断增加药物浓度的情况下使病毒在人外周血单核细胞和MT-2细胞中连续传代，评估了1型HIV（HIV-1）对这些化合物产生耐药性的可能性。经过两个或更多轮感染后，高度耐药的HIV-1变异株在复制的病毒群体中占主导地位。这些耐药变异株对(-)-FTC、(-)-BCH-189及其(+)同源物具有交叉耐药性，但对2',3'-二脱氧胞苷、3'-叠氮-3'-脱氧胸苷、3'-氟-3'-脱氧胸苷、2',3'-二脱氧肌苷、膦甲酸盐、TIBO化合物R82150和双（杂芳基）哌嗪衍生物U-87201E仍敏感。与来自亲本药物敏感病毒的酶相比，从耐药病毒颗粒衍生的逆转录酶对FTC和BCH-189的5'-三磷酸的敏感性降低了15至50倍。从耐药病毒中扩增的逆转录酶基因的DNA序列分析一致确定密码子184处发生了从甲硫氨酸（ATG）到缬氨酸（GTG或GTA）或异亮氨酸（ATA）的突变。对一名接受(-)-BCH-189治疗4个月的患者扩增的逆转录酶进行序列分析，结果显示甲硫氨酸184到缬氨酸（GTG）突变与亲本基因型的混合，表明甲硫氨酸184突变可在体内发生。
