Emamzadeh-Fard Sahra, Esmaeeli Shooka, Arefi Khalilullah, Moradbeigi Majedeh, Heidari Behnam, Fard Sahar E, Paydary Koosha, Seyedalinaghi Seyedahmad
Iranian Research Center for HIV/AIDS (IRCHA), Imam Khomeini Hospital, Keshavarz Blvd, Tehran, Iran.
Infect Disord Drug Targets. 2013 Oct;13(5):330-6. doi: 10.2174/1871526514666140321104049.
Anti-retroviral drug resistance evolves as an inevitable consequence of expanded combination Anti-retroviral Therapy (cART). According to each drug class, resistance mutations may occur due to the infidel nature of HIV reverse transcriptase (RT) and inadequate drug pressures. Correspondingly, resistance to Nucleoside Reverse Transcriptase Inhibitors (NRTIs) occurs due to incorporation impairment of the agent or its removal from the elongating viral DNA chain. With regard to Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), resistance mutations may alter residues of the RT hydrophobic pocket and demonstrate high level of cross resistance. However, resistance to Protease Inhibitors requires complex accumulation of primary and secondary mutations that substitute amino acids in proximity to the viral protease active site. Resistance to novel entry inhibitors may also evolve as a result of mutations that affect the interactions between viral glycoprotein and CD4 or the chemokine receptors. According to the current studies, future drug initiative programs should consider agents that possess higher genetic barrier toward resistance for ascertaining adequate drug efficacy among patients who have failed first-line regimens.
抗逆转录病毒药物耐药性的出现是联合抗逆转录病毒疗法（cART）广泛应用的必然结果。根据药物类别不同，由于HIV逆转录酶（RT）的不忠实特性以及药物压力不足，可能会发生耐药性突变。相应地，对核苷类逆转录酶抑制剂（NRTIs）的耐药性是由于药物掺入受损或其从延长的病毒DNA链中被清除所致。对于非核苷类逆转录酶抑制剂（NNRTIs），耐药性突变可能会改变RT疏水口袋的残基，并表现出高水平的交叉耐药性。然而，对蛋白酶抑制剂的耐药性需要在病毒蛋白酶活性位点附近替代氨基酸的一级和二级突变的复杂积累。对新型进入抑制剂的耐药性也可能因影响病毒糖蛋白与CD4或趋化因子受体之间相互作用的突变而产生。根据目前的研究，未来的药物研发计划应考虑对耐药性具有更高遗传屏障的药物，以便在一线治疗方案失败的患者中确保足够的药物疗效。
