HP-PRRSV is attenuated by de-optimization of codon pair bias in its RNA-dependent RNA polymerase nsp9 gene

Gao, Li; Wang, Lianghai; Huang, Chen; Yang, Longlong; Guo, Xue-Kun; Yu, Zhibin; Liu, Yihao; Yang, Peng; Feng, Wen-hai

doi:10.1016/j.virol.2015.07.012

Cited by 32 publications

(26 citation statements)

References 53 publications

(65 reference statements)

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“…The effects of the mutation in NSP10 will be investigated in the future. Previous work has shown that HP-PRRSV can be attenuated by deoptimizing the codon pair bias in the RdRp of PRRSV, demonstrating that changing codon bias can alter the virulence and replication capacity of PRRSV (22). However, the mechanism by which this leads to attenuation is unclear.…”

Section: Discussionmentioning

confidence: 99%

Two Residues in NSP9 Contribute to the Enhanced Replication and Pathogenicity of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus

Zhao

Gao

Xiong

et al. 2018

J Virol

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Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) possesses greater replicative capacity and pathogenicity than classical PRRSV. However, the factors that lead to enhanced replication and pathogenicity remain unclear. In our study, an alignment of all available full-length sequences of North American-type PRRSVs ( = 204) revealed two consistent amino acid mutations that differed between HP-PRRSV and classical PRRSV and were located at positions 519 and 544 in nonstructural protein 9. Next, a series of mutant viruses with either single or double amino acid replacements were generated from HP-PRRSV HuN4 and classical PRRSV CH-1a infectious cDNA clones. Deletion of either of the amino acids led to a complete loss of virus viability. In both Marc-145 and porcine alveolar macrophages, the replicative efficiencies of mutant viruses based on HuN4 were reduced compared to the parent, whereas the replication level of CH-1a-derived mutant viruses was increased. Plaque growth assays showed clear differences between mutant and parental viruses. In infected piglets, the pathogenicity of HuN4-derived mutant viruses, assessed through clinical symptoms, viral load in sera, histopathology examination, and thymus atrophy, was reduced. Our results indicate that the amino acids at positions 519 and 544 in NSP9 are involved in the replication efficiency of HP-PRRSV and contribute to enhanced pathogenicity. This study is the first to identify specific amino acids involved in PRRSV replication or pathogenicity. These findings will contribute to understanding the molecular mechanisms of PRRSV replication and pathogenicity, leading to better therapeutic and prognostic options to combat the virus. Porcine reproductive and respiratory syndrome (PRRS), caused by porcine reproductive and respiratory syndrome virus (PRRSV), is a significant threat to the global pig industry. Highly pathogenic PRRSV (HP-PRRSV) first emerged in China in 2006 and has subsequently spread across Asia, causing considerable damage to local economies. HP-PRRSV strains possess a greater replication capacity and higher pathogenicity than classical PRRSV strains, although the mechanisms that underlie these characteristics are unclear. In the present study, we identified two mutations in HP-PRRSV strains that distinguish them from classical PRRSV strains. Further experiments that swapped the two mutations in an HP-PRRSV strain and a classical PRRSV strain demonstrated that they are involved in the replication efficiency of the virus and its virulence. Our findings have important implications for understanding the molecular mechanisms of PRRSV replication and pathogenicity and also provide new avenues of research for the study of other viruses.

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Section: Discussionmentioning

confidence: 99%

Two Residues in NSP9 Contribute to the Enhanced Replication and Pathogenicity of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus

Zhao

Gao

Xiong

et al. 2018

J Virol

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“…These findings imply that other unknown factors may participate in this influence for the pathogenicity of PRRSV although the two amino acids in 586 and 592 of nsp9 are recognized as critical sites conferring the fatal virulence of HP-PRRSV in the current study. One example is that HP-PRRSV can be attenuated by de-optimization of codon pair bias in nsp9-coding region without any amino acid changes (Gao et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Nonstructural protein 9 residues 586 and 592 are critical sites in determining the replication efficiency and fatal virulence of the Chinese highly pathogenic porcine reproductive and respiratory syndrome virus

Zhou

Sun

et al. 2018

Virology

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The highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) has caused huge economic losses to the swine industry in China. Understanding the molecular basis in relation to the virulence of HP-PRRSV is essential for effectively controlling clinical infection and disease. In the current study, we constructed and rescued a serial of mutant viruses in nsp9 and nsp10 based on the differential amino acid sites between HP-PRRSV JXwn06 and LP-PRRSV HB-1/3.9. The replication efficiency in pulmonary alveolar macrophages (PAMs) and the pathogenicity of the mutant viruses for piglets were analyzed. Our results showed that the mutation of Thr to Ala in 586 and Ser to Thr in 592 of nsp9 decreased the replication efficiency of HP-PRRSV in PAMs, and could attenuate its virulence for piglets, suggesting that the residues 586 and 592 of nsp9 are critical sites natively in determining the fatal virulence of the Chinese HP-PRRSV for piglets.

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“…First, synonymous mutations are not necessarily neutral because of the phenotypic significance of codon (and codon pair) biases, as shown for picornaviruses (50,51,53,(209)(210)(211)(212), other positive-strand RNA viruses (213)(214)(215)(216)(217), and negative-strand RNA viruses (217)(218)(219)(220)(221)(222)(223). These biases may be due mainly to the effects on kinetics of translation (e.g., owing to uneven representation of tRNA species corresponding to different synonymous codons and to some features of the ribosome machinery [224]).…”

Section: (Relative) Neutrality Of Various Mutationsmentioning

confidence: 99%

Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

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Reproduction of RNA viruses is typically error-prone due to the infidelity of their replicative machinery and the usual lack of proofreading mechanisms. The error rates may be close to those that kill the virus. Consequently, populations of RNA viruses are represented by heterogeneous sets of genomes with various levels of fitness. This is especially consequential when viruses encounter various bottlenecks and new infections are initiated by a single or few deviating genomes. Nevertheless, RNA viruses are able to maintain their identity by conservation of major functional elements. This conservatism stems from genetic robustness or mutational tolerance, which is largely due to the functional degeneracy of many protein and RNA elements as well as to negative selection. Another relevant mechanism is the capacity to restore fitness after genetic damages, also based on replicative infidelity. Conversely, error-prone replication is a major tool that ensures viral evolvability. The potential for changes in debilitated genomes is much higher in small populations, because in the absence of stronger competitors low-fit genomes have a choice of various trajectories to wander along fitness landscapes. Thus, low-fit populations are inherently unstable, and it may be said that to run ahead it is useful to stumble. In this report, focusing on picornaviruses and also considering data from other RNA viruses, we review the biological relevance and mechanisms of various alterations of viral RNA genomes as well as pathways and mechanisms of rehabilitation after loss of fitness. The relationships among mutational robustness, resilience, and evolvability of viral RNA genomes are discussed.

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HP-PRRSV is attenuated by de-optimization of codon pair bias in its RNA-dependent RNA polymerase nsp9 gene

Cited by 32 publications

References 53 publications

Two Residues in NSP9 Contribute to the Enhanced Replication and Pathogenicity of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus

Two Residues in NSP9 Contribute to the Enhanced Replication and Pathogenicity of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus

Nonstructural protein 9 residues 586 and 592 are critical sites in determining the replication efficiency and fatal virulence of the Chinese highly pathogenic porcine reproductive and respiratory syndrome virus

Emergency Services of Viral RNAs: Repair and Remodeling

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