Loss of Sendai virus C protein leads to accumulation of RIG-I immunostimulatory defective interfering RNA

Sánchez-Aparicio, María Teresa; Garcin, Dominique; Rice, Charles M.; Kolakofsky, Daniel; Garcı́a-Sastre, Adolfo; Baum, Alina

doi:10.1099/jgv.0.000815

Cited by 24 publications

(21 citation statements)

References 54 publications

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“…In addition, sequencing analysis of nasopharyngeal samples from influenza virus-infected humans or infections in vitro with human metapneumovirus or measles virus (MeV) revealed multiple DVG species in these infections [51][52][53] . However, different from deletion and point mutation DVGs, copy-back DVGs are frequently found in discrete dominant populations in an infected cell or tissue, and the same copy-back DVG seems to arise in independent infections with the same parental virus 54,55 or during infections with different virus strains 56 . The demonstration of hotspots for the generation of copyback DVGs from respiratory syncytial virus (RSV) and the identification of specific nucleotides that determine where copy-back DVGs rejoin further demonstrate that the generation of copy-back DVGs is not completely random, but instead that specific sequences encoded in the viral genome direct or facilitate their formation 50 in some infections, DVG generation is not a completely stochastic process and, instead, virus-encoded sequences favour the production and/or amplification of predominant DVGs.…”

Section: Mechanisms Of Dvg Generationmentioning

confidence: 99%

“…Mutations in the influenza virus nuclear export protein (NEP, also known as NS2), which regulates the synthesis of complementary RNA, result in enhanced DVG production 66 . Similarly, deletion or mutations of the paramyxovirus C proteins that regulate template switching from antigenomic to genomic replication result in enhanced copy-back DVG production 53,56 (Fig. 2a).…”

Section: Role Of Viral Proteinsmentioning

confidence: 99%

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Defective viral genomes are key drivers of the virus–host interaction

2019

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Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are beginning to appreciate the surprising versatility of viral genomes and how replicationcompetent and -defective virus variants can provide means for adaptation, immune escape and virus perpetuation. This Review summarizes current knowledge of the types of defective viral genomes generated during the replication of RNA viruses and the functions that they carry out. We highlight the universality and diversity of defective viral genomes during infections and discuss their predicted role in maintaining a fit virus population, their impact on human and animal health, and their potential to be harnessed as antiviral tools. Review ARticleNATuRe MicRoBiology extinction interfere with replication of a wild-type viral genome 29,30 . Hypermutations and mutations leading to frame shifts also result in defective viruses 31 (Fig. 1a). One example is mutations introduced by the cellular protein APOBEC3G into pro-retroviruses 32 . APOBEC3G deaminates deoxycytidine nucleotides in the viral DNA, leading to hypermutations that interfere with the ability of the viral genome to integrate into the host genome and replicate. Interestingly, in opposition to an interfering activity for these mutated pro-viruses, it has been proposed that defective proviruses enhance fitness and that complementation among them drives viral persistence and pathogenesis 33,34 .Deletions. The genomic viral species most commonly referred to as DVGs are truncated viral genomes resulting from large internal deletions occurring during viral replication. Deletion DVGs tend to bear single large truncations that remove several or all essential genes required for self-propagation while retaining 5′ and 3′ ends as well as other RNA structural elements required for polymerase binding, replication and/or packaging [35][36][37] . Multiple variants also exist, including DVGs that can be described as 'mosaic' in that they appear to be the result of multiple recombination and rearrangement events, including deletions, insertions, duplications and even inversions of parts of the genome [38][39][40] (Fig. 1b). Copy-backs.Copy-back and snap-back DVGs are rearranged genomes in which a sequence is duplicated in reverse complement to create theoretical stem-like structures (panhandle structures for copy-back DVGs or hairpin structures for snap-back DVGs) 41-43 . Copy-back DVGs have been reported in many negative-sense (ns) RNA viruses and are generated from the 5′ end of the genome in a process that produces DVGs with complementary 3′ and 5′ termini 44,45 . If the complementary region of the DVG comprises almost the entire sequence, the DVG can be further characterized as a snap-back DVG 43 (Fig. 1c). Copy-back DVGs are predicted to be generated when the viral RNA-dependent RNA polymerase (RdRP) detaches from the template and reattaches to the nascent strand, copying back the end of the genome 42,46 .

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Section: Mechanisms Of Dvg Generationmentioning

confidence: 99%

Section: Role Of Viral Proteinsmentioning

confidence: 99%

Defective viral genomes are key drivers of the virus–host interaction

2019

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“…However, we found no clear correlation between GFP expression and SeV protein in IFN- β -GFP THFs infected with SeV particles ( Figure 7 A). SeV is known to produce and package defective viral genomes (DVGs) recognized by RIG-I during SeV infection, and these may be responsible for IFN- β production in cells infected with SeV particles ( Baum et al., 2010 ; Sanchez-Aparicio et al., 2017 ). We infected IFN- β -GFP THFs with SeV particles and sorted GFP high and GFP low cells before harvesting RNA.…”

Section: Resultsmentioning

confidence: 99%

Virus-Intrinsic Differences and Heterogeneous IRF3 Activation Influence IFN-Independent Antiviral Protection

et al. 2020

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“…Viral factors such as low-fidelity viral polymerases can lead to the over production of DVGs due to increased recombination rates (46), whilst the loss of viral accessory proteins, such as the C protein of Sendai virus, can also promote the accumulation of DVGs (47,48).…”

Section: Downloaded Frommentioning

confidence: 99%

Innate Intracellular Antiviral Responses Restrict the Amplification of Defective Virus Genomes of Parainfluenza Virus 5

Wignall-Fleming

Vasou

Young

et al. 2020

J Virol

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During the replication of parainfluenza virus 5 (PIV5), copyback defective virus genomes (DVGs) are erroneously produced and are packaged into “infectious” virus particles. Copyback DVGs are the primary inducers of innate intracellular responses, including the interferon (IFN) response. While DVGs can interfere with the replication of nondefective (ND) virus genomes and activate the IFN-induction cascade before ND PIV5 can block the production of IFN, we demonstrate that the converse is also true, i.e., high levels of ND virus can block the ability of DVGs to activate the IFN-induction cascade. By following the replication and amplification of DVGs in A549 cells that are deficient in a variety of innate intracellular antiviral responses, we show that DVGs induce an uncharacterized IFN-independent innate response(s) that limits their replication. High-throughput sequencing was used to characterize the molecular structure of copyback DVGs. While there appears to be no sequence-specific break or rejoining points for the generation of copyback DVGs, our findings suggest there are region, size, and/or structural preferences selected for during for their amplification. IMPORTANCE Copyback defective virus genomes (DVGs) are powerful inducers of innate immune responses both in vitro and in vivo. They impact the outcome of natural infections, may help drive virus‐host coevolution, and promote virus persistence. Due to their potent interfering and immunostimulatory properties, DVGs may also be used therapeutically as antivirals and vaccine adjuvants. However, little is known of the host cell restrictions which limit their amplification. We show here that the generation of copyback DVGs readily occurs during parainfluenza virus 5 (PIV5) replication, but that their subsequent amplification is restricted by the induction of innate intracellular responses. Molecular characterization of PIV5 copyback DVGs suggests that while there are no genome sequence-specific breaks or rejoin points for the generation of copyback DVGs, genome region, size, and structural preferences are selected for during their evolution and amplification.

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Loss of Sendai virus C protein leads to accumulation of RIG-I immunostimulatory defective interfering RNA

Cited by 24 publications

References 54 publications

Defective viral genomes are key drivers of the virus–host interaction

Defective viral genomes are key drivers of the virus–host interaction

Virus-Intrinsic Differences and Heterogeneous IRF3 Activation Influence IFN-Independent Antiviral Protection

Innate Intracellular Antiviral Responses Restrict the Amplification of Defective Virus Genomes of Parainfluenza Virus 5

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