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Viruses ; 14(5)2022 04 28.
Article in English | MEDLINE | ID: covidwho-1884366


Genetic recombination in RNA viruses is an important evolutionary mechanism. It contributes to population diversity, host/tissue adaptation, and compromises vaccine efficacy. Both the molecular mechanism and initial products of recombination are relatively poorly understood. We used an established poliovirus-based in vitro recombination assay to investigate the roles of sequence identity and RNA structure, implicated or inferred from an analysis of circulating recombinant viruses, in the process. In addition, we used next-generation sequencing to investigate the early products of recombination after cellular coinfection with different poliovirus serotypes. In independent studies, we find no evidence for a role for RNA identity or structure in determining recombination junctions location. Instead, genome function and fitness are of greater importance in determining the identity of recombinant progeny. These studies provide further insights into this important evolutionary mechanism and emphasize the critical nature of the selection process on a mixed virus population.

Enterovirus Infections , Enterovirus , Poliovirus , Antigens, Viral , Enterovirus/genetics , Genome, Viral , Humans , Poliovirus/genetics , RNA , Recombination, Genetic
Cell ; 184(25): 6037-6051.e14, 2021 12 09.
Article in English | MEDLINE | ID: covidwho-1520752


RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.

Capsid Proteins/genetics , Defective Interfering Viruses/metabolism , Virus Replication/drug effects , Administration, Intranasal , Animals , Antiviral Agents/pharmacology , Broadly Neutralizing Antibodies/immunology , Broadly Neutralizing Antibodies/pharmacology , COVID-19 , Capsid Proteins/metabolism , Cell Line , Defective Interfering Viruses/pathogenicity , Disease Models, Animal , Genome, Viral/genetics , Humans , Influenza, Human , Interferons/metabolism , Male , Mice , Mice, Inbred C57BL , Poliovirus/genetics , Poliovirus/metabolism , Respiratory Tract Infections/virology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity