Hepatitis C virus variants resistant to macrocyclic NS3-4A inhibitors subvert IFN-β induction by efficient MAVS cleavage

Welsch, Christoph; Haselow, Katrin; Gouttenoire, Jérôme; Schneider, Markus; Morikawa, Kenichi; Martínez, Yolanda; Susser, S.; Sarrazin, Christoph; Zeuzem, Stefan; Antes, Iris; Moradpour, Darius; Lange, Christian

doi:10.1016/j.jhep.2014.11.009

Cited by 12 publications

(22 citation statements)

References 22 publications

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“…A recent study reports that nsp4, a 3C-like viral proteinase, cleaves MAVS protein into small products and thus leads to the abolishment of IFN production [19]. A similar strategy is also utilized by hepatitis C virus [47], and so it seems clear that many viruses often target not only proteins but also RNAs to counteract antiviral responses of hosts. The SARS-CoV nsp1 protein binds to the 40S ribosome to inactivate translation and also induces a template-dependent cleavage of mRNA [48].…”

Section: Discussionmentioning

confidence: 99%

Nonstructural Protein 11 of Porcine Reproductive and Respiratory Syndrome Virus Suppresses Both MAVS and RIG-I Expression as One of the Mechanisms to Antagonize Type I Interferon Production

Sun

Han

et al. 2016

PLoS ONE

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Type I interferons (IFN-α/β) play a key role in antiviral defense, and porcine reproductive and respiratory syndrome virus (PRRSV) is known to down-regulate the IFN response in virus-infected cells and pigs. In this study, we showed that the overexpression of nsp11 of PRRSV induced a strong suppression of IFN production. Nsp11 suppressed both IRF3 and NF-κB activities when stimulated with a dsRNA analogue and TNF-α, respectively. This suppression was RLR dependent, since the transcripts and proteins of MAVS and RIG-I, two critical factors in RLR-mediated pathway, were both found to be reduced in the presence of overexpressed nsp11. Since nsp11 is an endoribonuclease (EndoU), the structure function relationship was examined using a series of nsp11 EndoU mutant plasmids. The mutants that impaired the EndoU activity failed to suppress IFN and led to the normal expression of MAVS. Seven single amino acid substitutions (4 in subdomain A and 3 in subdomain B) plus one insertion (frame-shift in nsp11) were then introduced into PRRSV infectious cDNA clones to generate nsp11 mutant viruses. Unfortunately, all EndoU knock-out nsp11 mutant viruses appeared replication-defective and no progenies were produced. Three mutations in EndoU subdomain A expressed the N and nsp2/3 proteins but their infectivity diminished after 2 passages. Taken together, our data show that PRRSV nsp11 endoribonuclease activity is critical for both viral replication and IFN antagonism. More importantly, the endoribonuclease activity of nsp11 demonstrates the substrate specificity towards MAVS and RIG-I (transcripts and proteins) over p65 and IRF3 in the context of gene transfection and overexpression. This is likely a mechanism of nsp11 suppression of type I IFN production.

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Section: Discussionmentioning

confidence: 99%

Nonstructural Protein 11 of Porcine Reproductive and Respiratory Syndrome Virus Suppresses Both MAVS and RIG-I Expression as One of the Mechanisms to Antagonize Type I Interferon Production

Sun

Han

et al. 2016

PLoS ONE

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“…Viruses inhibit MAVS-mediated antiviral signaling via several mechanisms. Hepatitis C virus uses its NS3-4A to cleave MAVS to block MAVS-dependent antiviral signaling (Welsch et al, 2015). Rotavirus NS1 protein inhibits MAVS expression to attenuate its signaling (Nandi et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Functional motifs responsible for human metapneumovirus M2-2-mediated innate immune evasion

Chen

Deng

et al. 2016

Virology

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Human metapneumovirus (hMPV) is a major cause of lower respiratory infection in young children. Repeated infections occur throughout life, but its immune evasion mechanisms are largely unknown. We recently found that hMPV M2-2 protein elicits immune evasion by targeting mitochondrial antiviral-signaling protein (MAVS), an antiviral signaling molecule. However, the molecular mechanisms underlying such inhibition are not known. Our mutagenesis studies revealed that PDZ-binding motifs, 29-DEMI-32 and 39-KEALSDGI-46, located in an immune inhibitory region of M2-2, are responsible for M2-2-mediated immune evasion. We also found both motifs prevent TRAF5 and TRAF6, the MAVS downstream adaptors, to be recruited to MAVS, while the motif 39-KEALSDGI-46 also blocks TRAF3 migrating to MAVS. In parallel, these TRAFs are important in activating transcription factors NF-kB and/or IRF-3 by hMPV. Our findings collectively demonstrate that M2-2 uses its PDZ motifs to launch the hMPV immune evasion through blocking the interaction of MAVS and its downstream TRAFs.

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“…The model initially proposed by Brass et al 3 suggests NS3 helix α 0 and the transmembrane α-helix of NS4A involved in proper positioning of the serine protease active site on the ER membrane with important consequences for viral polyprotein processing and proteolytic targeting of host factors. The strict positioning of the protease active site with respect to the membrane confers a high degree of selectivity to potential cellular trans -cleavage substrates, such as MAVS 5 6 or the membrane-associated peroxidase GPx8 23 . Our observations may add to this model in that they reflect pathways for information transfer between functional important sites in NS3 with helix α 18 as a novel regulatory element.…”

Section: Discussionmentioning

confidence: 99%

“…The development of chronic hepatitis C depends largely on the capability of NS3p to cleave antiviral host proteins. A prominent example is the cleavage (and inactivation) of mitochondrial antiviral-signaling protein MAVS (also called Cardif, VISA, and IPS-1), which impedes MAVS-mediated induction of type I interferons by the retinoic acid-inducible gene I (RIG-I) signaling pathway 5 6 .…”

mentioning

confidence: 99%

Natural HCV variants with increased replicative fitness due to NS3 helicase mutations in the C-terminal helix α18

Stroß

Shimakami

Haselow

et al. 2016

Sci Rep

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High replicative fitness is a general determinant of a multidrug resistance phenotype and may explain lower sensitivity to direct-acting antiviral agents (DAAs) in some hepatitis C virus genotypes. Genetic diversity in the molecular target site of peptidomimetic NS3 protease inhibitors could impact variant replicative fitness and potentially add to virologic treatment failure. We selected NS3 helicase residues near the protease natural substrate in the NS3 domain interface and identified natural variants from a public database. Sequence diversity among different genotypes was identified and subsequently analyzed for potential effects of helicase variants on protein structure and function, and phenotypic effects on RNA replication and DAA resistance. We found increased replicative fitness in particular for amino acid substitutions at the NS3 helicase C-terminal helix α18. A network of strongly coupled residue pairs is identified. Helix α18 is part of this regulatory network and connects several NS3 functional elements involved in RNA replication. Among all genotypes we found distinct sequence diversity at helix α18 in particular for the most difficult-to-treat genotype 3. Our data suggest sequence diversity with implications for virus replicative fitness due to natural variants in helicase helix α18.

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Hepatitis C virus variants resistant to macrocyclic NS3-4A inhibitors subvert IFN-β induction by efficient MAVS cleavage

Cited by 12 publications

References 22 publications

Nonstructural Protein 11 of Porcine Reproductive and Respiratory Syndrome Virus Suppresses Both MAVS and RIG-I Expression as One of the Mechanisms to Antagonize Type I Interferon Production

Nonstructural Protein 11 of Porcine Reproductive and Respiratory Syndrome Virus Suppresses Both MAVS and RIG-I Expression as One of the Mechanisms to Antagonize Type I Interferon Production

Functional motifs responsible for human metapneumovirus M2-2-mediated innate immune evasion

Natural HCV variants with increased replicative fitness due to NS3 helicase mutations in the C-terminal helix α18

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