Hepatitis C Virus RNA Replication

Lohmann, Volker

doi:10.1007/978-3-642-27340-7_7

Cited by 107 publications

(137 citation statements)

References 185 publications

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“…2). However, as indicated, the charge and volume of the phosphate group added to the surface of the HCV NS5B could affect its dimerization or interactions with another factor(s) [1,23].…”

Section: Structural Implications Of Serine Residues Phosphorylation Amentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

“…The expression of the viral RNA produces a polyprotein precursor, which is proteolytically cleaved into mature proteins, comprising structural and nonstructural (NS) polypeptides [1]. Whereas the structural proteins will package the viral RNA into progeny virions, the nonstructural proteins will assemble into a protein multi-subunit RNA replication complex on intracellular membranous webs [1]. Among the viral NS proteins, NS5B, the critical RNA-dependent RNA polymerase (RdRP), has been a target of intense research to promote understanding of the complex regulation of its enzymatic activities during RNA synthesis [1].…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation at the N-terminal finger subdomain of a viral RNA-dependent RNA polymerase

Hernández

Figueroa

Correa

et al. 2015

Biochemical and Biophysical Research Communications

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“…2). However, as indicated, the charge and volume of the phosphate group added to the surface of the HCV NS5B could affect its dimerization or interactions with another factor(s) [1,23].…”

Section: Structural Implications Of Serine Residues Phosphorylation Amentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phosphorylation at the N-terminal finger subdomain of a viral RNA-dependent RNA polymerase

Hernández

Figueroa

Correa

et al. 2015

Biochemical and Biophysical Research Communications

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“…Much has been learned about the mechanism of HCV RNA replication as well as the host factors and cellular structures involved in this process ( [17,18,[46][47][48][49] and references therein) (reviewed in [50,51]). However, there is room to learn about the mechanisms regulating HCV RNA translation vs. replication vs. virion packaging as well as the biogenesis of the viral replication complex.…”

Section: Hcv Rna Replicationmentioning

confidence: 99%

Future landscape of hepatitis C research – Basic, translational and clinical perspectives

Moradpour

Grakoui

Manns

2016

Journal of Hepatology

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With the latest all-oral interferon- and ribavirin-free regimens based on direct acting antivirals against the hepatitis C virus (HCV), sustained virological response rates of >90% are achieved, which is equivalent to cure. This has become possible for all genotypes and all subgroups of patients, including many of the most difficult-to-treat populations so far. Since a prophylactic HCV vaccine is not yet available, control of HCV infection will for the time being have to rely on the use of effective and safe antiviral treatments as well as their accessibility and affordability. Different approaches may apply to different parts of the world, eradication of HCV representing a major long-term goal. Whether hepatitis C becomes the first chronic viral infection to be eradicated without a prophylactic vaccine remains to be shown. Here, we briefly summarize advances in the molecular virology of hepatitis C, highlight lessons of biological relevance that were learned through the study of HCV, and its translational and clinical implications. We have also listed selected unsolved challenges, emphasizing that HCV is a unique model and that advances in this direction may yield knowledge of broad biological significance, novel technologies and insights into related important human pathogens.

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“…The structural proteins include core, which forms the viral nucleocapsid, and the envelope glycoproteins E1 and E2, which mediate early cell entry events (3). NS2 and p7 (a viroporin) play crucial roles in virus assembly/egress (4)(5)(6), and the remaining nonstructural proteins, NS3, NS4A, NS4B, NS5A, and NS5B, form replication complexes, which synthesize both plus-and minus-strand viral RNAs (7). HCV is classified into seven major genetic groups and further subdivided into numerous subtypes (1,8).…”

mentioning

confidence: 99%

Role of Conserved E2 Residue W420 in Receptor Binding and Hepatitis C Virus Infection

Cowton

Angus

Cole

et al. 2016

J Virol

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Hepatitis C virus (HCV) enters cells via interactions with several host factors, a key one being that between the viral E2 envelope glycoprotein and the CD81 receptor. We previously identified E2 tryptophan residue 420 (W420) as an essential CD81-binding residue. However, the importance of W420 in the context of the native virion is unknown, as those previous studies predate the infectious HCV cell culture (cell culture-derived HCV [HCVcc]) system. Here, we introduced four separate mutations (F, Y, A, or R) at position 420 within the infectious HCVcc JFH-1 genome and characterized their effects on the viral life cycle. While all mutations reduced E2-CD81 binding, only two (W420A and W420R) reduced HCVcc infectivity. Further analyses of mutants with hydrophobic residues (F or Y) found that interactions with the receptors SR-BI and CD81 were modulated, which in turn determined the viral uptake route. Both mutant viruses were significantly less dependent on SR-BI, and its lipid transfer activity, for virus entry. Furthermore, these viruses were resistant to the drug erlotinib, which targets epidermal growth factor receptor (EGFR) (a host cofactor for HCV entry) and also blocks SR-BI-dependent high-density lipoprotein (HDL)-mediated enhancement of virus entry. Together, our data indicate a model where an alteration at position 420 causes a subtle change in the E2 conformation that prevents interaction with SR-BI and increases accessibility to the CD81-binding site, in turn favoring a particular internalization route. These results further show that a hydrophobic residue with a strong preference for tryptophan at position 420 is important, both functionally and structurally, to provide an additional hydrophobic anchor to stabilize the E2-CD81 interaction. IMPORTANCEHepatitis C virus (HCV) is a leading cause of liver disease, causing up to 500,000 deaths annually. The first step in the viral life cycle is the entry process. This study investigates the role of a highly conserved residue, tryptophan residue 420, of the viral glycoprotein E2 in this process. We analyzed the effect of changing this residue in the virus and confirmed that this region is important for binding to the CD81 receptor. Furthermore, alteration of this residue modulated interactions with the SR-BI receptor, and changes to these key interactions were found to affect the virus internalization route involving the host cofactor EGFR. Our results also show that the nature of the amino acid at this position is important functionally and structurally to provide an anchor point to stabilize the E2-CD81 interaction.

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Hepatitis C Virus RNA Replication

Cited by 107 publications

References 185 publications

Phosphorylation at the N-terminal finger subdomain of a viral RNA-dependent RNA polymerase

Phosphorylation at the N-terminal finger subdomain of a viral RNA-dependent RNA polymerase

Future landscape of hepatitis C research – Basic, translational and clinical perspectives

Role of Conserved E2 Residue W420 in Receptor Binding and Hepatitis C Virus Infection

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