The significance of recurrent de novo amino acid substitutions that emerged during chronic SARS-CoV-2 infection: an observational study.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-09-01 Epub Date: 2024-08-14 DOI:10.1016/j.ebiom.2024.105273

Jonathan Daniel Ip, Wing-Ming Chu, Wan-Mui Chan, Allen Wing-Ho Chu, Rhoda Cheuk-Ying Leung, Qi Peng, Anthony Raymond Tam, Brian Pui-Chun Chan, Jian-Piao Cai, Kwok-Yung Yuen, Kin-Hang Kok, Yi Shi, Ivan Fan-Ngai Hung, Kelvin Kai-Wang To

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Abstract

Background: De novo amino acid substitutions (DNS) frequently emerge among immunocompromised patients with chronic SARS-CoV-2 infection. While previous studies have reported these DNS, their significance has not been systematically studied.

Methods: We performed a review of DNS that emerged during chronic SARS-CoV-2 infection. We searched PubMed until June 2023 using the keywords "(SARS-CoV-2 or COVID-19) and (mutation or sequencing) and ((prolonged infection) or (chronic infection) or (long term))". We included patients with chronic SARS-CoV-2 infection who had SARS-CoV-2 sequencing performed for at least 3 time points over at least 60 days. We also included 4 additional SARS-CoV-2 patients with chronic infection of our hospital not reported previously. We determined recurrent DNS that has appeared in multiple patients and determined the significance of these mutations among epidemiologically-significant variants.

Findings: A total of 34 cases were analyzed, including 30 that were published previously and 4 from our hospital. Twenty two DNS appeared in ≥3 patients, with 14 (64%) belonging to lineage-defining mutations (LDMs) of epidemiologically-significant variants and 10 (45%) emerging among chronically-infected patients before the appearance of the corresponding variant. Notably, nsp9-T35I substitution (Orf1a T4175I) emerged in all three patients with BA.2.2 infection in 2022 before the appearance of Variants of Interest that carry nsp9-T35I as LDM (EG.5 and BA.2.86/JN.1). Structural analysis suggests that nsp9-T35I substitution may affect nsp9-nsp12 interaction, which could be critical for the function of the replication and transcription complex.

Interpretation: DNS that emerges recurrently in different chronically-infected patients may be used as a marker for potential epidemiologically-significant variants.

Funding: Theme-Based Research Scheme [T11/709/21-N] of the Research Grants Council (See acknowledgements for full list).

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慢性 SARS-CoV-2 感染期间反复出现的新氨基酸替代的意义：一项观察性研究。

背景：在慢性 SARS-CoV-2 感染的免疫功能低下患者中经常出现新的氨基酸替代（DNS）。虽然以前的研究已经报道了这些 DNS，但尚未对其意义进行系统研究：我们对 SARS-CoV-2 慢性感染期间出现的 DNS 进行了综述。我们使用关键词"（SARS-CoV-2 或 COVID-19）和（突变或测序）和（（长期感染）或（慢性感染）或（长期））"对 PubMed 进行了检索，直至 2023 年 6 月。我们纳入了至少在 60 天内对至少 3 个时间点进行了 SARS-CoV-2 测序的慢性 SARS-CoV-2 感染患者。我们还纳入了本医院另外 4 名以前未报告过的 SARS-CoV-2 慢性感染患者。我们确定了在多名患者中反复出现的 DNS，并确定了这些变异在具有流行病学意义的变异中的重要性：我们共分析了 34 例病例，其中 30 例是以前发表过的，4 例来自本医院。22个DNS出现在≥3名患者中，其中14个（64%）属于流行病学意义变异的系定义变异（LDM），10个（45%）出现在相应变异出现前的慢性感染患者中。值得注意的是，在携带 nsp9-T35I 的 LDM 感兴趣变异体（EG.5 和 BA.2.86/JN.1）出现之前，2022 年 BA.2.2 感染的所有三名患者中都出现了 nsp9-T35I 替换（Orf1a T4175I）。结构分析表明，nsp9-T35I 的取代可能会影响 nsp9-nsp12 的相互作用，这可能对复制和转录复合体的功能至关重要：在不同慢性感染患者中反复出现的 DNS 可作为潜在流行病学意义变异的标记：基金：研究资助委员会主题研究计划[T11/709/21-N]（完整清单见致谢）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.