人类免疫缺陷病毒 1 型逆转录酶连接域突变的组合：评估对核苷和非核苷逆转录酶抑制剂耐药性的影响。
Combinations of mutations in the connection domain of human immunodeficiency virus type 1 reverse transcriptase: assessing the impact on nucleoside and nonnucleoside reverse transcriptase inhibitor resistance.
机构信息
Monogram Biosciences, South San Francisco, CA 94080, USA.
出版信息
Antimicrob Agents Chemother. 2010 May;54(5):1973-80. doi: 10.1128/AAC.00870-09. Epub 2010 Mar 1.
Recent reports have described the effect of mutations in the connection and RNase H domains of reverse transcriptase (RT) on nucleoside and nonnucleoside reverse transcriptase inhibitor (NRTI and NNRTI, respectively) resistance in the presence of thymidine analog resistance mutations (TAMs) and NNRTI mutations (J. H. Brehm, D. Koontz, J. D. Meteer, V. Pathak, N. Sluis-Cremer, and J. W. Mellors, J. Virol. 81:7852-7859, 2007; K. A. Delviks-Frankenberry, G. N. Nikolenko, R. Barr, and V. K. Pathak, J. Virol. 81:6837-6845, 2007; G. N. Nikolenko, K. A. Delviks-Frankenberry, S. Palmer, F. Maldarelli, M. J. Fivash, Jr., J. M. Coffin, and V. K. Pathak, Proc. Natl. Acad. Sci. U. S. A. 104:317-322, 2007; G. N. Nikolenko, S. Palmer, F. Maldarelli, J. W. Mellors, J. M. Coffin, and V. K. Pathak, Proc. Natl. Acad. Sci. U. S. A. 102:2093-2098, 2005; and S. H. Yap, C. W. Sheen, J. Fahey, M. Zanin, D. Tyssen, V. D. Lima, B. Wynhoven, M. Kuiper, N. Sluis-Cremer, P. R. Harrigan, and G. Tachedjian, PLoS Med. 4:e335, 2007). In the present study, novel mutations in the connection domain of RT (T369I/V), first identified in patient-derived viruses, were characterized, and their effects on NNRTI and NNRTI susceptibility were determined. Furthermore, the effect of N348I on NRTI and NNRTI resistance was confirmed. HIV-1 with either N348I or T369I/V demonstrated reduced susceptibility to nevirapine (NVP), efavirenz (EFV), delaviridine (DLV), and zidovudine (ZDV) compared to wild-type HIV-1. However, HIV-1 with T369I and N348I demonstrated 10- to 60-fold resistance to these same drugs. In clinical samples, these two connection domain RT mutations were predominantly observed in viruses containing TAMs and NNRTI mutations and did not alter the susceptible-resistant classifications of these samples. Introduction of T369I, N348I, or T369I/N348I also reduced replication capacity (RC). These observations suggest that it may be of scientific interest to test these mutations against new NNRTI candidates.
最近的报告描述了逆转录酶（RT）连接和 RNase H 结构域中的突变对核苷和非核苷逆转录酶抑制剂（NRTI 和 NNRTI，分别）耐药性的影响，这些耐药性与胸苷类似物耐药突变（TAMs）和 NNRTI 突变（J. H. Brehm、D. Koontz、J. D. Meteer、V. Pathak、N. Sluis-Cremer 和 J. W. Mellors，J. Virol. 81:7852-7859, 2007；K. A. Delviks-Frankenberry、G. N. Nikolenko、R. Barr 和 V. K. Pathak，J. Virol. 81:6837-6845, 2007；G. N. Nikolenko、K. A. Delviks-Frankenberry、S. Palmer、F. Maldarelli、M. J. Fivash, Jr.、J. M. Coffin 和 V. K. Pathak，Proc. Natl. Acad. Sci. U. S. A. 104:317-322, 2007；G. N. Nikolenko、S. Palmer、F. Maldarelli、J. W. Mellors、J. M. Coffin 和 V. K. Pathak，Proc. Natl. Acad. Sci. U. S. A. 102:2093-2098, 2005；和 S. H. Yap、C. W. Sheen、J. Fahey、M. Zanin、D. Tyssen、V. D. Lima、B. Wynhoven、M. Kuiper、N. Sluis-Cremer、P. R. Harrigan 和 G. Tachedjian，PLoS Med. 4:e335, 2007）。在本研究中，首先在患者来源的病毒中鉴定出了 RT 连接域中的新突变（T369I/V），并对其 NNRTI 和 NNRTI 敏感性进行了表征。此外，还证实了 N348I 对 NRTI 和 NNRTI 耐药性的影响。与野生型 HIV-1 相比，具有 N348I 或 T369I/V 的 HIV-1 对奈韦拉平（NVP）、依非韦伦（EFV）、地拉韦啶（DLV）和齐多夫定（ZDV）的敏感性降低。然而，具有 T369I 和 N348I 的 HIV-1 对这些相同药物的耐药性增加了 10 到 60 倍。在临床样本中，这两种连接域 RT 突变主要存在于含有 TAMs 和 NNRTI 突变的病毒中，并且不改变这些样本的敏感耐药分类。引入 T369I、N348I 或 T369I/N348I 也降低了复制能力（RC）。这些观察结果表明，针对新的 NNRTI 候选药物对这些突变进行测试可能具有科学意义。
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