Iyidogan Pinar, Anderson Karen S
Department of Pharmacology, School of Medicine, Yale University, New Haven, CT, USA.
Antivir Chem Chemother. 2014 Dec 16;23(6):217-22. doi: 10.3851/IMP2628.
Since its approval for clinical use in 2001, tenofovir (TFV) has become one of the most frequently prescribed nucleotide analogues used in combination with other antiretroviral agents against HIV-1 infection. Although reverse transcriptase inhibitors (RTIs) including TFV have been shown to be highly potent with reasonable safety profiles in the clinic, drug resistance hinders the effectiveness of current therapies and even causes treatment failure. Therefore, understanding the resistance mechanisms of RT and exploring the potential antiviral synergy between the different RTIs in combination therapies against the resistance mechanisms would greatly improve the long-term efficacy of existing and future regimens. We have studied the pyrophosphorolytic removal of TFV, a major resistance mechanism that RT utilizes, from two different viral sequences and observed interesting outcomes associated with the sequence context. Furthermore, addition of efavirenz, a non-nucleoside RTI, inhibits this removal process confirming the synergistic antiviral effects. This article highlights our recently published work on the viral sequence context contributing to the study of anti-HIV drug resistance in conjunction with the benefits of combining various RTIs that may have been neglected previously.
自2001年被批准用于临床以来，替诺福韦（TFV）已成为最常被处方的核苷酸类似物之一，与其他抗逆转录病毒药物联合用于对抗HIV-1感染。尽管包括TFV在内的逆转录酶抑制剂（RTIs）在临床上已显示出高效且安全性良好，但耐药性阻碍了当前疗法的有效性，甚至导致治疗失败。因此，了解逆转录酶的耐药机制，并探索联合疗法中不同RTIs之间针对耐药机制的潜在抗病毒协同作用，将极大地提高现有及未来治疗方案的长期疗效。我们研究了逆转录酶利用的主要耐药机制——从两种不同病毒序列中焦磷酸解去除替诺福韦，并观察到与序列背景相关的有趣结果。此外，添加非核苷类RTI依非韦伦可抑制这一去除过程，证实了抗病毒协同效应。本文重点介绍了我们最近发表的关于病毒序列背景的研究工作，该研究有助于抗HIV耐药性的研究，同时也阐述了联合使用各种RTIs的益处，而这些益处此前可能被忽视了。
