Multimodal Research Area, Microbiology and Diagnostics of Immunology Unit, Bambino Gesù Children Hospital IRCCS, Rome, Italy.
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Commun Biol. 2022 Dec 15;5(1):1376. doi: 10.1038/s42003-022-04322-8.
Little is known about SARS-CoV-2 evolution under Molnupiravir and Paxlovid, the only antivirals approved for COVID-19 treatment. By investigating SARS-CoV-2 variability in 8 Molnupiravir-treated, 7 Paxlovid-treated and 5 drug-naïve individuals at 4 time-points (Days 0-2-5-7), a higher genetic distance is found under Molnupiravir pressure compared to Paxlovid and no-drug pressure (nucleotide-substitutions/site mean±Standard error: 18.7 × 10 ± 2.1 × 10 vs. 3.3 × 10 ± 0.8 × 10 vs. 3.1 × 10 ± 0.8 × 10, P = 0.0003), peaking between Day 2 and 5. Molnupiravir drives the emergence of more G-A and C-T transitions than other mutations (P = 0.031). SARS-CoV-2 selective evolution under Molnupiravir pressure does not differ from that under Paxlovid or no-drug pressure, except for orf8 (dN > dS, P = 0.001); few amino acid mutations are enriched at specific sites. No RNA-dependent RNA polymerase (RdRp) or main proteases (Mpro) mutations conferring resistance to Molnupiravir or Paxlovid are found. This proof-of-concept study defines the SARS-CoV-2 within-host evolution during antiviral treatment, confirming higher in vivo variability induced by Molnupiravir compared to Paxlovid and drug-naive, albeit not resulting in apparent mutation selection.
关于莫努匹韦和奈玛特韦/利托那韦（唯一批准用于 COVID-19 治疗的抗病毒药物）作用下的 SARS-CoV-2 进化，人们知之甚少。本研究通过在 4 个时间点（第 0、2、5、7 天）对 8 名接受莫努匹韦治疗、7 名接受奈玛特韦/利托那韦治疗和 5 名未接受药物治疗的个体的 SARS-CoV-2 变异性进行调查，发现莫努匹韦压力下的遗传距离高于奈玛特韦/利托那韦压力和无药物压力（核苷酸替换/位点平均值±标准误差：18.7×10±2.1×10 对 3.3×10±0.8×10 对 3.1×10±0.8×10，P=0.0003），在第 2 天到第 5 天之间达到峰值。莫努匹韦诱导的 G-A 和 C-T 转换突变多于其他突变（P=0.031）。莫努匹韦压力下的 SARS-CoV-2 选择性进化与奈玛特韦/利托那韦压力或无药物压力下的进化没有差异，除了orf8（dN＞dS，P=0.001）；在特定位置富集了少数氨基酸突变。未发现对莫努匹韦或奈玛特韦/利托那韦具有耐药性的 RNA 依赖性 RNA 聚合酶（RdRp）或主要蛋白酶（Mpro）突变。本概念验证研究定义了抗病毒治疗期间 SARS-CoV-2 的体内进化，证实了与奈玛特韦/利托那韦相比，莫努匹韦在体内诱导的变异性更高，尽管没有导致明显的突变选择。
