气候变化领域集成服务门户(CCPortal): Rescue of codon-pair deoptimized respiratory syncytial virus by the emergence of genomes with very large internal deletions that complemented replication

CCPortal

DOI	10.1073/pnas.2020969118
	Rescue of codon-pair deoptimized respiratory syncytial virus by the emergence of genomes with very large internal deletions that complemented replication
	Le Nouën C.; McCarty T.; Yang L.; Brown M.; Wimmer E.; Collins P.L.; Buchholz U.J.
发表日期	2021
ISSN	00278424
卷号	118 期号:13
英文摘要	Recoding viral genomes by introducing numerous synonymous but suboptimal codon pairs—called codon-pair deoptimization (CPD)—provides new types of live-attenuated vaccine candidates. The large number of nucleotide changes resulting from CPD should provide genetic stability to the attenuating phenotype, but this has not been rigorously tested. Human respiratory syncytial virus in which the G and F surface glycoprotein ORFs were CPD (called Min B) was temperature-sensitive and highly restricted in vitro. When subjected to selective pressure by serial passage at increasing temperatures, Min B substantially regained expression of F and replication fitness. Whole-genome deep sequencing showed many point mutations scattered across the genome, including one combination of six linked point mutations. However, their reintroduction into Min B provided minimal rescue. Further analysis revealed viral genomes bearing very large internal deletions (LD genomes) that accumulated after only a few passages. The deletions relocated the CPD F gene to the first or second promoter-proximal gene position. LD genomes amplified de novo in Min B–infected cells were encapsidated, expressed high levels of F, and complemented Min B replication in trans. This study provides insight on a variation of the adaptability of a debilitated negative-strand RNA virus, namely the generation of defective minihelper viruses to overcome its restriction. This is in contrast to the common “defective interfering particles” that interfere with the replication of the virus from which they originated. To our knowledge, defective genomes that promote rather than inhibit replication have not been reported before in RNA viruses. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Codon-pair deoptimization; Defective genomes; Genetic stability; Negative-strand RNA virus; Respiratory syncytial virus
语种	英语
scopus关键词	Article; codon; codon pair deoptimization; defective virus; F gene; G gene; gene deletion; gene expression; genetic stability; helper virus; Human respiratory syncytial virus; negative-strand RNA virus; nonhuman; open reading frame; point mutation; priority journal; promoter region; very large internal deletion; virus gene; virus genome; virus replication; whole genome sequencing; article; gene amplification; genetic stability; high throughput sequencing; virus culture; virus genome; virus replication
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180080
作者单位	RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, United States; Research and Development Division, Pacific Biosciences Inc., Menlo Park, CA 94025, United States; Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY 11794, United States
推荐引用方式 GB/T 7714	Le Nouën C.,McCarty T.,Yang L.,et al. Rescue of codon-pair deoptimized respiratory syncytial virus by the emergence of genomes with very large internal deletions that complemented replication[J],2021,118(13).
APA	Le Nouën C..,McCarty T..,Yang L..,Brown M..,Wimmer E..,...&Buchholz U.J..(2021).Rescue of codon-pair deoptimized respiratory syncytial virus by the emergence of genomes with very large internal deletions that complemented replication.Proceedings of the National Academy of Sciences of the United States of America,118(13).
MLA	Le Nouën C.,et al."Rescue of codon-pair deoptimized respiratory syncytial virus by the emergence of genomes with very large internal deletions that complemented replication".Proceedings of the National Academy of Sciences of the United States of America 118.13(2021).