Conserved Glycine 33 Residue in Flexible Domain I of Hepatitis C Virus Core Protein Is Critical for Virus Infectivity

Angus, Allan G. N.; Loquet, Antoine; Stack, Seamus; Dalrymple, David; Gatherer, Derek; Pénin, François; Patel, Arvind H.

doi:10.1128/jvi.05452-11

Cited by 17 publications

(26 citation statements)

References 46 publications

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“…In agreement with previous observation, the amino acid metabolism in patients with hepatitis B virus (HBV) infection is significantly changed [46]. Conserved glycine 33 residue in flexible domain I of HCV core protein is critical for its virulent activity [47]. A previous study has demonstrated that HBV E-antigen physically associates with receptor interaction serine/threonine protein kinase 2 [48].…”

Section: Discussionsupporting

confidence: 85%

A Metabolomics Profiling Study in Hand-Foot-and-Mouth Disease and Modulated Pathways of Clinical Intervention Using Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

Lü

Liu

Ding

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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Hand-foot-and-mouth disease (HFMD), with poorly understood pathogenesis, has become a major public health threat across Asia Pacific. In order to characterize the metabolic changes of HFMD and to unravel the regulatory role of clinical intervention, we have performed a metabolomics approach in a clinical trial. In this study, metabolites profiling was performed by liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) platform from the HFMD clinical patient samples. The outcome of this study suggested that 31 endogenous metabolites were mainly involved and showed marked perturbation in HFMD patients. In addition, combination therapy intervention showed normalized tendency in HFMD patients in differential pathway. Taken together, these results indicate that metabolomics approach can be used as a complementary tool for the detection and the study of the etiology of HFMD.

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Section: Discussionsupporting

confidence: 85%

A Metabolomics Profiling Study in Hand-Foot-and-Mouth Disease and Modulated Pathways of Clinical Intervention Using Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

Lü

Liu

Ding

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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“…However, in the absence of structural data, we cannot exclude the possibility that mutations of other, also non-basic, residues in the same region will have an impact on core-NS5A interactions. Especially, if we take into consideration how important is for virus infectivity to maintain a close contact between two distant amino acids in HCV core as it has been demonstrated for residues G33 and F24 [75]. Next, we confirmed that core interacts with NS5A through the four N-terminal basic amino acids in cells expressing full-length HCV genome.…”

Section: Discussionsupporting

confidence: 68%

HCV Core Residues Critical for Infectivity Are Also Involved in Core-NS5A Complex Formation

et al. 2014

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Hepatitis C virus (HCV) infection is a major cause of liver disease. The molecular machinery of HCV assembly and particle release remains obscure. A better understanding of the assembly events might reveal new potential antiviral strategies. It was suggested that the nonstructural protein 5A (NS5A), an attractive recent drug target, participates in the production of infectious particles as a result of its interaction with the HCV core protein. However, prior to the present study, the NS5A-binding site in the viral core remained unknown. We found that the D1 domain of core contains the NS5A-binding site with the strongest interacting capacity in the basic P38-K74 cluster. We also demonstrated that the N-terminal basic residues of core at positions 50, 51, 59 and 62 were required for NS5A binding. Analysis of all substitution combinations of R50A, K51A, R59A, and R62A, in the context of the HCVcc system, showed that single, double, triple, and quadruple mutants were fully competent for viral RNA replication, but deficient in secretion of viral particles. Furthermore, we found that the extracellular and intracellular infectivity of all the mutants was abolished, suggesting a defect in the formation of infectious particles. Importantly, we showed that the interaction between the single and quadruple core mutants and NS5A was impaired in cells expressing full-length HCV genome. Interestingly, mutations of the four basic residues of core did not alter the association of core or NS5A with lipid droplets. This study showed for the first time that basic residues in the D1 domain of core that are critical for the formation of infectious extracellular and intracellular particles also play a role in core-NS5A interactions.

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“…The plasmid pJFH1, containing the full‐length genomic cDNA sequence of the HCV genotype 2a strain and the N17/JFH1 plasmid were linearized using XbaI enzyme (New England Biolabs) and then treated with Mung Bean Nuclease (NEB) prior purification. Linearized plasmids were used as a template to generate in vitro transcribed RNA using MEGAscript T7 (Life Technologies, Milan, Italy).…”

Section: Methodsmentioning

confidence: 99%

17,β‐estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle

Magrì

Barbaglia

Foglia

et al. 2016

Liver International

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Background & AimsOestrogen and oestrogen‐mediated signalling protect from hepatitis C virus through incompletely understood mechanisms. We aimed to ascertain which phase(s) of hepatitis C virus life cycle is/are affected by oestrogens.MethodsHuh7 cells infected with the JFH1 virus (genotype 2a) were exposed to dehydroepiandrosterone, testosterone, progesterone and 17β‐estradiol (tested with/without its receptor antagonist fulvestrant). Dose–response curves were established to calculate half maximal inhibitory concentration values. To dissect how 17β‐estradiol interferes with phases of hepatitis C virus life cycle, its effects were measured on the hepatitis C virus pseudo‐particle system (viral entry), the subgenomic replicon N17/JFH1 and the replicon cell line Huh7‐J17 (viral replication). Finally, in a dual‐step infection model, infectious supernatants, collected from infected cells exposed to hormones, were used to infect naïve cells.ResultsProgesterone and testosterone showed no inhibitory effect on hepatitis C virus; dehydroepiandrosterone was only mildly inhibitory. In contrast, 17β‐estradiol inhibited infection by 64%‐67% (IC 50 values 140‐160 nmol/L). Fulvestrant reverted the inhibition by 17β‐estradiol in a dose‐dependent manner. 17β‐estradiol exerted only a slight inhibition (<20%) on hepatitis C virus pseudo‐particles, and had no effect on cells either transiently or stably (Huh7‐J17 cells) expressing the N17/JFH1 replicon. In the dual‐step infection model, a significant half maximal inhibitory concentration decline occurred between primary (134 nmol/L) and secondary (100 nmol/L) infections (P=.02), with extracellular hepatitis C virus RNA and infectivity being reduced to a higher degree in comparison to its intracellular counterpart.Conclusions17β‐estradiol inhibits hepatitis C virus acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the hepatitis C virus life cycle.

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Conserved Glycine 33 Residue in Flexible Domain I of Hepatitis C Virus Core Protein Is Critical for Virus Infectivity

Cited by 17 publications

References 46 publications

A Metabolomics Profiling Study in Hand-Foot-and-Mouth Disease and Modulated Pathways of Clinical Intervention Using Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

A Metabolomics Profiling Study in Hand-Foot-and-Mouth Disease and Modulated Pathways of Clinical Intervention Using Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

HCV Core Residues Critical for Infectivity Are Also Involved in Core-NS5A Complex Formation

17,β‐estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle

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