Retroviral Replication Laboratory, National Cancer Institute, Frederick, Maryland, USA.
Clinical Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0150021. doi: 10.1128/AAC.01500-21. Epub 2021 Nov 1.
Resistance to anti-HIV drugs has been a problem from the beginning of antiviral drug treatments. The recent expansion of combination antiretroviral therapy worldwide has led to an increase in resistance to antiretrovirals; understanding the mechanisms of resistance is increasingly important. In this study, we analyzed reverse transcriptase (RT) variants based on sequences derived from an individual who had low-level rebound viremia while undergoing therapy with abacavir, azidothymidine (AZT) (zidovudine), and (-)-l-2',3'-dideoxy-3'-thiacytidine (3TC) (lamivudine). The RT had mutations at positions 64, 67, 70, 184, and 219 and a threonine insertion after amino acid 69 in RT. The virus remained partially susceptible to the nucleoside RT inhibitor (NRTI) regimen. We show how these mutations affect the ability of NRTIs to inhibit DNA synthesis by RT. The presence of the inserted threonine reduced the susceptibility of the RT mutant to inhibition by tenofovir.
抗 HIV 药物的耐药性从抗病毒药物治疗开始就是一个问题。最近，全球联合抗逆转录病毒疗法的扩展导致了抗逆转录病毒药物的耐药性增加；了解耐药机制变得越来越重要。在这项研究中，我们分析了逆转录酶 (RT) 的变体，这些变体基于一个个体的序列，该个体在接受阿巴卡韦、齐多夫定 (AZT) (叠氮胸苷) 和 (-)-l-2',3'-双脱氧-3'-硫代胞苷 (3TC) (拉米夫定) 治疗时出现低水平病毒反弹血症。RT 具有位置 64、67、70、184 和 219 处的突变以及 RT 中氨基酸 69 后的苏氨酸插入。病毒对核苷逆转录酶抑制剂 (NRTI) 方案仍具有部分敏感性。我们展示了这些突变如何影响 NRTIs 抑制 RT 合成 DNA 的能力。插入苏氨酸的存在降低了 RT 突变体对替诺福韦抑制的敏感性。
