Domain I of the 5′ non-translated genomic region in coxsackievirus B3 RNA is not required for productive replication

Jaramillo, Lee; Smithee, Shane; Tracy, Steven; Chapman, Nora M.

doi:10.1016/j.virol.2016.05.021

Cited by 7 publications

(8 citation statements)

References 21 publications

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“…On the other hand, it is not always correct to consider the mutational loss of the capacity to trigger an obvious cytopathic effect (CPE) (e.g., a lack of plaque-forming activity) sufficient evidence for killing of the virus, as usually done. For example, as already mentioned, complete destruction of the CVB3 replicative element oriL (99) or cre (149), resulting in a loss of cytopathic activity, is nevertheless compatible with viral viability: such viruses are able to grow, though with a greatly diminished efficiency, causing persistent, noncytopathic infections. An FMDV variant that accumulated various debilitating mutations during multiple plaque-to-plaque (bottlenecking) passages represented another example of conversion of a lytic virus into a noncytocidal one (290).…”

Section: (Relative) Neutrality Of Various Mutationsmentioning

confidence: 93%

“…The interaction between these ligands is important for the initiation of the synthesis of both the viral (positive) and complementary (negative) RNA strands (89,93,(95)(96)(97)(98). It was recently shown that (at least in the case of coxsackievirus B3 [CVB3]) oriL, which is required for efficient genome replication, is not indispensable for viral viability: its removal does not kill the virus but rather decreases the efficiency of its RNA replication ϳ10 5 -fold (99). It should be noticed, however, that the nonessentiality of oriL has so far been shown only for this particular virus (see also a reservation at the end of this section).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: (Relative) Neutrality Of Various Mutationsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

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“…Natural deletions within the 5′NCR of EV-B RNA populations can affect functional secondary-structural elements of the RNA domain I (cloverleaf, CL) 9 – 11 altering formation or stability of viral replication complexes and consequently decreasing genomic replicative capacities of 5′TD viral RNA forms 12 – 14 . Moreover, it was evidenced that the 5′triphosphorylated cloverleaf structure of CVB3 RNA is sufficient to induce a type 1 IFN response by the RIG-I signalling pathway 10 .…”

Section: Introductionmentioning

confidence: 99%

Major 5′terminally deleted enterovirus populations modulate type I IFN response in acute myocarditis patients and in human cultured cardiomyocytes

Glenet

N’Guyen

Mirand³

et al. 2020

Sci Rep

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the french enterovirus Myocarditis Study Group (feMSG) * Major 5′terminally deleted (5′TD) group-B enterovirus (EV-B) populations were identified in heart biopsies of patients with fulminant myocarditis or dilated cardiomyopathy suggesting that these 5′TD forms are key drivers of host-cell interaction in EV cardiac infections. To date, early emergence of EV-B 5′TD forms and its impact on type 1 IFN response during acute myocarditis remains unknown. Using quantitative RACE-PCR assay, we identified major EV-B 5′tD RnA populations in plasma or heart samples of acute myocarditis cases. Deletions identified within the 5′ non-coding region of EV-B populations only affected secondary-structural elements of genomic RNA domain I and were distinguished in two major groups based on the extent of RnA structural deletions. proportions of these two respective EV-B 5′tD population groups were positively or negatively correlated with IFN-β levels in plasma samples of myocarditis patients. Transfection of synthetic CVB3/28 RNAs harboring various 5′terminal full-length or deleted sequences into human cultured cardiomyocytes demonstrated that viral genomic RnA domain i possessed essential immunomodulatory secondarystructural elements responsible for IFN-β pathway induction. Overall, our results highlight the early emergence of major EVB-TD populations which deletions affecting secondary-structures of RNA domain i can modulate innate immune sensing mechanisms in cardiomyocytes of patients with acute myocarditis. Group-B Enteroviruses (EV-B) belong to the Picornaviridae family and are recognized as major causes of aseptic meningitis, upper or lower respiratory tract infections and acute myocarditis cases diagnosed in neonates, infants and young adults 1,2. Between 10-20% of acute myocarditis cases will evolve into chronic myocarditis as well as dilated cardiomyopathy (DCM, prevalence = 7 cases / 100,000, second leading cause of heart transplantation worldwide after ischemic heart disease) 1. EV-B RNA genome is approximately 7,400 nucleotides (nt) in length and is flanked at the 5′ end by a highly conserved non-coding region (5′NCR) that is crucial for the initiation of the viral replication and translation activities 3. A study in 2008 of heart tissue from a patient who died of fulminant myocarditis demonstrated the presence of a group B Coxsackie virus type 2 (CVB-2) population with partial deletions at the 5′ terminus and proceeding inward 4. Similar findings had been described following CVB-3 replication in cell cultures and in mice 5,6. Bouin et al.7 identified EV-B populations characterized by 5′NCR RNA deletions ranging from 15 to 48 nt

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“…Nonetheless, accumulation of longer 5′ terminal deletions appears to have limits, as passage of the CVB3-TD virus with a terminal 49-nucleotide deletion (CVB3-TD50) in primary cell cultures and in mice failed to create a population of TDs with deletions greater than 49 nucleotides [ 50 , 61 ]. Despite our observation that naturally occurring 5′ TD deletions larger than 49 nucleotides do not occur (or, more likely, are exceedingly rare), we created a CVB3-TD genome deleted through stem-loop d (CVB3-TD78) that retained the ability to replicate in HeLa cells and generate the virus, albeit with a 100,000-fold reduction in virus particle production [ 69 ]. We suggest that the lack of observed stable populations of TD CVB genomes with deletions greater than 49 nucleotides from the 5′ end is more likely to be the result of reduced fitness within the maelstrom of constantly occurring TD RNAs in an infected cell, rather than TDs without stem-loop d ever occurring.…”

Section: Discovery and Characterization Of A Novel Late-stage “Noninf...mentioning

confidence: 99%

Persistent Enterovirus Infection: Little Deletions, Long Infections

Chapman

2022

Vaccines

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Enteroviruses have now been shown to persist in cell cultures and in vivo by a novel mechanism involving the deletion of varying amounts of the 5′ terminal genomic region termed domain I (also known as the cloverleaf). Molecular clones of coxsackievirus B3 (CVB3) genomes with 5′ terminal deletions (TD) of varying length allow the study of these mutant populations, which are able to replicate in the complete absence of wildtype virus genomes. The study of TD enteroviruses has revealed numerous significant differences from canonical enteroviral biology. The deletions appear and become the dominant population when an enterovirus replicates in quiescent cell populations, but can also occur if one of the cis-acting replication elements of the genome (CRE-2C) is artificially mutated in the element’s stem and loop structures. This review discusses how the TD genomes arise, how they interact with the host, and their effects on host biology.

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Domain I of the 5′ non-translated genomic region in coxsackievirus B3 RNA is not required for productive replication

Cited by 7 publications

References 21 publications

Emergency Services of Viral RNAs: Repair and Remodeling

Emergency Services of Viral RNAs: Repair and Remodeling

Major 5′terminally deleted enterovirus populations modulate type I IFN response in acute myocarditis patients and in human cultured cardiomyocytes

Persistent Enterovirus Infection: Little Deletions, Long Infections

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