Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Systems Genomics Section, NIH/NIAID/DIR/LPD, Bethesda, MD, USA.
Nat Commun. 2024 Sep 18;15(1):7999. doi: 10.1038/s41467-024-51924-3.
We investigated the impact of antiviral treatment on the emergence of SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n = 15). All patients received remdesivir and some also received nirmatrelvir-ritonavir (n = 3) or therapeutic monoclonal antibodies (n = 4). Sequence analysis showed that nine patients carried viruses with mutations in the nsp12 (RNA dependent RNA polymerase), while four had viruses with nsp5 (3C protease) mutations. Infectious SARS-CoV-2 with a double mutation in nsp5 (T169I) and nsp12 (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis from a patient sequentially treated with nirmatrelvir-ritonavir and remdesivir. In vitro characterization confirmed its decreased sensitivity to remdesivir and nirmatrelvir, which was overcome by combined antiviral treatment. Studies in golden Syrian hamsters demonstrated efficient transmission to contact animals. This study documents the isolation of SARS-CoV-2 carrying resistance mutations to both nirmatrelvir and remdesivir from a patient and demonstrates its transmissibility in vivo.
我们研究了在免疫功能低下患者持续性感染期间，抗病毒治疗对 SARS-CoV-2 耐药性出现的影响（n=15）。所有患者均接受瑞德西韦治疗，部分患者还接受奈玛特韦/利托那韦（n=3）或单克隆抗体治疗（n=4）。序列分析显示，9 名患者携带 nsp12（RNA 依赖的 RNA 聚合酶）突变的病毒，4 名患者携带 nsp5（3C 蛋白酶）突变的病毒。从一名先后接受奈玛特韦/利托那韦和瑞德西韦治疗的患者的呼吸道分泌物中，在初次 COVID-19 诊断后 77 天，分离到带有 nsp5（T169I）和 nsp12（V792I）双重突变的传染性 SARS-CoV-2。体外特性分析证实其对瑞德西韦和奈玛特韦的敏感性降低，但联合抗病毒治疗可克服这种降低。金黄地鼠研究表明其具有向接触动物高效传播的能力。本研究从患者中分离到同时携带对奈玛特韦和瑞德西韦耐药性突变的 SARS-CoV-2，并证实其在体内的传染性。
