Effect of mutation in the hepatitis C virus nonstructural 5B region on HCV replication

Okura, Izumi; Horiike, Norio; Michitaka, Kojiro; Onji, Morikazu

doi:10.1007/s00535-003-1321-6

Cited by 4 publications

(4 citation statements)

References 38 publications

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“…This is similar to the effect of the L241-i-S242 at the downstream edge of Motif A in PV. Near the N-terminal end of Motif C in HCV (HCV T312), the mutation D311A characterizes chronic hepatitis (52). Mutation at the edge of a highly conserved structure seems to have a substantial effect on the viral life cycle.…”

Section: Hmc Discussionmentioning

confidence: 99%

Highly similar structural frames link the template tunnel and NTP entry tunnel to the exterior surface in RNA-dependent RNA polymerases

Lang

Zemła

Zhou

2012

Nucleic Acids Research

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RNA-dependent RNA polymerase (RdRp) is essential to viral replication and is therefore one of the primary targets of countermeasures against these dangerous infectious agents. Development of broad-spectrum therapeutics targeting polymerases has been hampered by the extreme sequence variability of these sequences. RdRps range in length from 400–800 residues, yet contain only ∼20 residues that are conserved in most species. In this study, we made structure-based comparisons that are independent of sequence composition using a recently developed algorithm. We identified residue-to-residue correspondences of multiple protein structures and created (two-dimensional) structure-based alignment maps of 37 polymerase structures that provide both sequence and structure details. Using these maps, we determined that ∼75% of each polymerase species consists of seven protein segments, each of which has high structural similarity to segments in other species, though they are widely divergent in sequence composition and order. We define each of these segments as a ‘homomorph’, and each includes (though most are much larger than) the well-known conserved polymerase motifs. All homomorphs contact the template tunnel or nucleoside triphosphate (NTP) entry tunnel and the exterior of the protein, suggesting they constitute a structural and functional skeleton common among the polymerases.

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Section: Hmc Discussionmentioning

confidence: 99%

Highly similar structural frames link the template tunnel and NTP entry tunnel to the exterior surface in RNA-dependent RNA polymerases

Lang

Zemła

Zhou

2012

Nucleic Acids Research

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“…is a matter of controversy. Some authors have reported that the presence of mutations in NS5B were associated with a decreased viral load in non-transplanted patients (27,47), but these findings have not been confirmed by others (39,48). In fact, the lower viral load in these patients might reflect the better control of HCV by the immune system.…”

Section: Discussionmentioning

confidence: 53%

Evolution of the NS3 and NS5B Regions of the Hepatitis C Virus During Disease Recurrence After Liver Transplantation

Massaguer

Ramírez

Carrión

et al. 2007

American Journal of Transplantation

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In patients with hepatitis C virus (HCV)-related cirrhosis, infection recurrence is universal after liver transplantation (LT). The relevance of host and virusrelated factors on the outcome of hepatitis C recurrence is poorly understood. This study analyzed the relationship between the genetic evolution of the NonStructural (NS)3 protease and NS5B polymerase regions of HCV and the severity of hepatitis C recurrence. Thirty-three patients were classified as having mild (n = 16) or severe recurrence (n = 17), according to the degree of fibrosis in liver biopsies obtained 1 year after transplantation. Viral load and consensus sequences of the NS3 and NS5B domains were determined in a pre-LT and in four post-LT sequential serum samples. At week 12 after LT, viremia was significantly higher in patients with severe recurrence. NS3 and NS5b regions evolved independently after LT. The genetic evolution of NS3 domain was not related to the severity of the recurrence. However, the diversification in the NS5B region later than 12 weeks after LT was greater in patients with mild than in those with severe recurrence, suggesting a stronger immune pressure in the first group. These observations highlight the complex interplay between viral evolution and clinical outcomes in the LT setting.

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“…Motif C contains highly conserved amino acid residues that represent specific signatures of each major group of RNA viruses. In motif C, the sequence GDD is conserved among polymerases of positive-strand RNA viruses, MDD belongs to retroviruses, GDN and SDD are conserved signature motifs of nonsegmented-negative stranded and segmented-negative stranded RNA viruses, respectively [8], whereas SDD is conserved in nidoviruses. High-resolution structures of RdRps of positive-and double-strand RNA viruses revealed clear similarities, despite sharing little sequence identity, suggesting an evolutionary link between the RdRps of these RNA viruses [15,20,31].…”

Section: Discussionmentioning

confidence: 99%

“…This structural conservation implies that palm domains of all RdRps may have evolved from a common, ancient ancestor. Motif C forms a "-strand, turn, -strand" structure that contains the highly conserved Gly-Asp-Asp (GDD) motif, with the aspartic acid residues exposed in the loop region found in RdRps, an RdRp hallmark [5,[8][9][10]. This structure is very similar in all classes of polymerases, and positions the two DD residues close to the conserved D of motif A [1].…”

mentioning

confidence: 99%

Mutational analysis of the SDD sequence motif of a PRRSV RNA-dependent RNA polymerase

Zhou

Zheng

Gao

et al. 2011

Sci. China Life Sci.

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The subgenomic mRNA transcription and genomic replication of the porcine reproductive and respiratory syndrome virus (PRRSV) are directed by the viral replicase. The replicase is expressed in the form of two polyproteins and is subsequently processed into smaller nonstructural proteins (nsps). nsp9, containing the viral replicase, has characteristic sequence motifs conserved among the RNA-dependent RNA polymerases (RdRp) of positive-strand (PS) RNA viruses. To test whether the conserved SDD motif can tolerate other conserved motifs of RNA viruses and the influence of every residue on RdRp catalytic activity, many amino acids substitutions were introduced into it. Only one nsp9 substitution, of serine by glycine (S3050G), could rescue mutant viruses. The rescued virus was genetically stable. Alteration of either aspartate residue was not tolerated, destroyed the polymerase activity, and abolished virus transcription, but did not eliminate virus replication. We also found that the SDD motif was essentially invariant for the signature sequence of PRRSV RdRp. It could not accommodate other conserved motifs found in other RNA viral polymerases, except the GDD motif, which is conserved in all the other PS RNA viruses. These findings indicated that nidoviruses are evolutionarily related to other PS RNA viruses. Our studies support the idea that the two aspartate residues of the SDD motif are critical and essential for PRRSV transcription and represent a sequence variant of the GDD motif in PS RNA viruses.

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Effect of mutation in the hepatitis C virus nonstructural 5B region on HCV replication

Abstract: HCV NS5B genotype-specific mutations in HCV genotype 1b may influence HCV replication.

Cited by 4 publications

References 38 publications

Highly similar structural frames link the template tunnel and NTP entry tunnel to the exterior surface in RNA-dependent RNA polymerases

Highly similar structural frames link the template tunnel and NTP entry tunnel to the exterior surface in RNA-dependent RNA polymerases

Evolution of the NS3 and NS5B Regions of the Hepatitis C Virus During Disease Recurrence After Liver Transplantation

Mutational analysis of the SDD sequence motif of a PRRSV RNA-dependent RNA polymerase

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