Flaviviral NS4b, chameleon and jack‐in‐the‐box roles in viral replication and pathogenesis, and a molecular target for antiviral intervention

Zmurko, Joanna; Neyts, Johan; Dallmeier, Kai

doi:10.1002/rmv.1835

Cited by 90 publications

(72 citation statements)

References 131 publications

(164 reference statements)

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“…The resulting topology model was very similar to those previously proposed or determined for other flaviviruses [42] (Fig 3B). Residue M26 maps to the N-terminal region located in the ER lumen.…”

Section: Resultssupporting

confidence: 83%

Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses

et al. 2016

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The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian/American ZIKV lineage.

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Section: Resultssupporting

confidence: 83%

Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses

et al. 2016

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“…We identified, however, a 36 nts/12aa deletion located on the NS4B coding region (N‐terminal part) of the genotype 1 isolate characterized in this study. By analogy with previous studies focusing on HCV and other Flaviviridae members, it is probable that pegivirus NS4B would play an important role on viral replication complex formation, associated with multiple interactions with cellular proteins as well . Investigation of biological impact of such deletion on viral cycle would require future studies involving, ideally, a cell line model able to support viral replication.…”

Section: Discussionmentioning

confidence: 94%

Human pegivirus isolates characterized by deep sequencing from hepatitis C virus‐RNA and human immunodeficiency virus‐RNA–positive blood donations, France

Jordier

Deligny

Barre

et al. 2018

Journal of Medical Virology

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Human pegivirus (HPgV, formerly GBV-C) is a member of the genus Pegivirus, family Flaviviridae. Despite its identification more than 20 years ago, both natural history and distribution of this viral group in human hosts remain under exploration. Analysis of HPgV genomes characterized up to now points out the scarcity of French pegivirus sequences in databases. To bring new data regarding HPgV genomic diversity, we investigated 16 French isolates obtained from hepatitis C virus-RNA and human immunodeficiency virus-RNA-positive blood donations following deep sequencing and coupled molecular protocols. Initial phylogenetic analysis of 5'-untranslated region (5'-UTR)/E2 partial sequences permitted to assign HPgV isolates to genotypes 2 (n = 15) and 1 (n = 1), with up to 16% genetic diversity observed for both regions considered. Seven nearly full-length representative genomes were characterized subsequently, with complete polyprotein coding sequences exhibiting up to 13% genetic diversity; closest nucleotide (nt) divergence with available HPgV sequences was in the range 7% to 11%. A 36 nts deletion located on the NS4B coding region (N-terminal part, 12 amino acids) of the genotype 1 HPgV genome characterized was identified, along with single nucleotide deletions in two genotype 2, 5'-UTR sequences.

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“…Numerous studies have examined inhibitors of the flaviviral NS4B protein 143,144 , a highly hydrophobic integral membrane protein 145 . NS4B mediates several interactions with other non-structural viral proteins and host proteins to modulate viral replication 146,147 .…”

Section: Ns4b Inhibitorsmentioning

confidence: 99%

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

Boldescu

Behnam

Vasilakis³

et al. 2017

Nat Rev Drug Discov

242

217

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Infections with flaviviruses, such as dengue, West Nile virus, and the recently re-emerging Zika virus are an increasing and probably lasting global risk. This review summarizes and comments on the opportunities for broad-spectrum agents that are active against a range of flaviviruses. Broad-spectrum activity would be particularly desirable as preparatory measure for the next flaviviral epidemic that could emerge from as-yet-unknown or neglected viruses. Potential target sites for broad-spectrum anti-flaviviral compounds include viral proteins and host mechanisms that are exploited by these viruses during entry and replication. A variety of compounds with broad-spectrum antiviral activity have already been identified by target-specific or phenotypic assays. For some other compound classes, broad-spectrum activity can be anticipated because of their mode of action and molecular target(s).

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Flaviviral NS4b, chameleon and jack‐in‐the‐box roles in viral replication and pathogenesis, and a molecular target for antiviral intervention

Cited by 90 publications

References 131 publications

Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses

Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses

Human pegivirus isolates characterized by deep sequencing from hepatitis C virus‐RNA and human immunodeficiency virus‐RNA–positive blood donations, France

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

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