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Impact of Synonymous Mutations on the Evolution, Fitness and Pathogenesis...
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Impact of Synonymous Mutations on the Evolution, Fitness and Pathogenesis of RNA Viruses

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "General Virology".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 5866

Special Issue Editor

Dr. Miguel A. Martínez

E-Mail Website
Guest Editor
IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), 08916 Badalona, Spain
Interests: My research interests are focused in understanding the molecular mechanisms implicated in human viruses pathogenesis. In the last two decades, I have being studying how the genetic variability of HIV-1 and HCV has influenced virus pathogenesis, immunogenicity and response to antiviral therapy. Recently, I have explored how synonymous codon mutations impact HIV-1 protein expression and virus replication capacity. Codon or codon pair biases and HIV-1 RNA dinucleotide frequencies (e.g., CpG/UpA) affect host innate response, virus latency and pathogenesis (reviewed in Jordan-Paiz, Franco and Martinez, Frontiers in Microbiology 2021; Martinez et al Nucleic Acids Research 2019; Martinez et al Trends in Microbiology 2016).
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Synonymous recoding of several RNA virus genomes has allowed the identification of previously unknown virus biological properties. Viral genome recoding by synonymous mutagenesis has identified new innate antiviral mechanisms and new functional virus genome structures. Moreover, synonymous recoding has demonstrated the relevance of codon and codon pair usage for the temporal regulation of viral gene expression, mutational robustness, and adaptability. Importantly, large-scale synonymous rewriting is not only decoding essential virus genome functions, but it is opening new therapeutic and diagnosis avenues that include the development of a new generation of RNA virus live-attenuated vaccines.

In this Special Issue of Viruses, I aim to discuss the recent developments and the general potential of synonymous recoding of RNA virus genomes to elucidate unknown aspects of the virus life cycle and to identify new therapeutic targets. I invite you to contribute your most recent research findings and insights with original research papers, technical advancements, or review articles.

Dr. Miguel A. Martínez
Guest Editor

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Keywords

  • RNA virus
  • synonymous mutations
  • virus phenotype
  • virus evolvability
  • virus fitness
  • synthetic genomes
  • genome rewriting
  • virus attenuation
  • vaccines

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Published Papers (3 papers)

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18 pages, 4577 KiB  
Article
Widespread Reassortment Contributes to Antigenic Shift in Bluetongue Viruses from South Africa
by Antoinette Van Schalkwyk, Peter Coetzee, Karen Ebersohn, Beate Von Teichman and Estelle Venter
Viruses 2023, 15(7), 1611; https://doi.org/10.3390/v15071611 - 23 Jul 2023
Viewed by 1602
Abstract
Bluetongue (BT), a viral disease of ruminants, is endemic throughout South Africa, where outbreaks of different serotypes occur. The predominant serotypes can differ annually due to herd immunity provided by annual vaccinations using a live attenuated vaccine (LAV). This has led to both [...] Read more.
Bluetongue (BT), a viral disease of ruminants, is endemic throughout South Africa, where outbreaks of different serotypes occur. The predominant serotypes can differ annually due to herd immunity provided by annual vaccinations using a live attenuated vaccine (LAV). This has led to both wild-type and vaccine strains co-circulating in the field, potentially leading to novel viral strains due to reassortment and recombination. Little is known about the molecular evolution of the virus in the field in South Africa. The purpose of this study was to investigate the genetic diversity of field strains of BTV in South Africa and to provide an initial assessment of the evolutionary processes shaping BTV genetic diversity in the field. Complete genomes of 35 field viruses belonging to 11 serotypes, collected from different regions of the country between 2011 and 2017, were sequenced. The sequences were phylogenetically analysed in relation to all the BTV sequences available from GenBank, including the LAVs and reference strains, resulting in the analyses and reassortment detection of 305 BTVs. Phylogenomic analysis indicated a geographical selection of the genome segments, irrespective of the serotype. Based on the initial assessment of the current genomic clades that circulate in South Africa, the selection for specific clades is prevalent in directing genome segment reassortment, which seems to exclude the vaccine strains and in multiple cases involves Segment-2 resulting in antigenic shift. Full article
(This article belongs to the Special Issue Impact of Synonymous Mutations on the Evolution, Fitness and Pathogenesis of RNA Viruses)
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20 pages, 4060 KiB  
Article
Deoptimization of FMDV P1 Region Results in Robust Serotype-Independent Viral Attenuation
by Gisselle N. Medina, Edward Spinard, Paul A. Azzinaro, Monica Rodriguez-Calzada, Joseph Gutkoska, Anna Kloc, Elizabeth A. Rieder, Bruce E. Taillon, Stephen Mueller, Teresa de los Santos and Fayna Diaz-San Segundo
Viruses 2023, 15(6), 1332; https://doi.org/10.3390/v15061332 - 6 Jun 2023
Cited by 3 | Viewed by 1854
Abstract
Foot-and-mouth disease (FMD), caused by the FMD virus (FMDV), is a highly contagious disease of cloven-hoofed livestock that can have severe economic impacts. Control and prevention strategies, including the development of improved vaccines, are urgently needed to effectively control FMD outbreaks in endemic [...] Read more.
Foot-and-mouth disease (FMD), caused by the FMD virus (FMDV), is a highly contagious disease of cloven-hoofed livestock that can have severe economic impacts. Control and prevention strategies, including the development of improved vaccines, are urgently needed to effectively control FMD outbreaks in endemic settings. Previously, we employed two distinct strategies (codon pair bias deoptimization (CPD) and codon bias deoptimization (CD)) to deoptimize various regions of the FMDV serotype A subtype A12 genome, which resulted in the development of an attenuated virus in vitro and in vivo, inducing varying levels of humoral responses. In the current study, we examined the versatility of the system by using CPD applied to the P1 capsid coding region of FMDV serotype A subtype, A24, and another serotype, Asia1. Viruses carrying recoded P1 (A24-P1Deopt or Asia1-P1Deopt) exhibited different degrees of attenuation (i.e., delayed viral growth kinetics and replication) in cultured cells. Studies in vivo using a mouse model of FMD demonstrated that inoculation with the A24-P1Deopt and Asia1-P1Deopt strains elicited a strong humoral immune response capable of offering protection against challenge with homologous wildtype (WT) viruses. However, different results were obtained in pigs. While clear attenuation was detected for both the A24-P1Deopt and Asia1-P1Deopt strains, only a limited induction of adaptive immunity and protection against challenge was detected, depending on the inoculated dose and serotype deoptimized. Our work demonstrates that while CPD of the P1 coding region attenuates viral strains of multiple FMDV serotypes/subtypes, a thorough assessment of virulence and induction of adaptive immunity in the natural host is required in each case in order to finely adjust the degree of deoptimization required for attenuation without affecting the induction of protective adaptive immune responses. Full article
(This article belongs to the Special Issue Impact of Synonymous Mutations on the Evolution, Fitness and Pathogenesis of RNA Viruses)
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15 pages, 3571 KiB  
Article
Evaluation of Potential In Vitro Recombination Events in Codon Deoptimized FMDV Strains
by Edward Spinard, Ian Fish, Paul A. Azzinaro, Monica Rodriguez-Calzada, Ethan J. Hartwig, George R. Smoliga, Aishwarya Mogulothu, Jonathan Arzt, Teresa de los Santos and Gisselle N. Medina
Viruses 2023, 15(3), 670; https://doi.org/10.3390/v15030670 - 2 Mar 2023
Cited by 3 | Viewed by 1929
Abstract
Codon deoptimization (CD) has been recently used as a possible strategy to derive foot-and-mouth disease (FMD) live-attenuated vaccine (LAV) candidates containing DIVA markers. However, reversion to virulence, or loss of DIVA, from possible recombination with wild-type (WT) strains has yet to be analyzed. [...] Read more.
Codon deoptimization (CD) has been recently used as a possible strategy to derive foot-and-mouth disease (FMD) live-attenuated vaccine (LAV) candidates containing DIVA markers. However, reversion to virulence, or loss of DIVA, from possible recombination with wild-type (WT) strains has yet to be analyzed. An in vitro assay was developed to quantitate the levels of recombination between WT and a prospective A24-P2P3 partially deoptimized LAV candidate. By using two genetically engineered non-infectious RNA templates, we demonstrate that recombination can occur within non-deoptimized viral genomic regions (i.e., 3′end of P3 region). The sequencing of single plaque recombinants revealed a variety of genome compositions, including full-length WT sequences at the consensus level and deoptimized sequences at the sub-consensus/consensus level within the 3′end of the P3 region. Notably, after further passage, two recombinants that contained deoptimized sequences evolved to WT. Overall, recombinants featuring large stretches of CD or DIVA markers were less fit than WT viruses. Our results indicate that the developed assay is a powerful tool to evaluate the recombination of FMDV genomes in vitro and should contribute to the improved design of FMDV codon deoptimized LAV candidates. Full article
(This article belongs to the Special Issue Impact of Synonymous Mutations on the Evolution, Fitness and Pathogenesis of RNA Viruses)
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