Hepatitis C virus infection protein network

Chassey, Benoı̂t de; Navratil, Vincent; Tafforeau, Lionel; Hiet, Marie–Sophie; Aublin-Gex, Anne; Agaugué, Sophie; Meiffren, Grégory; Pradezynski, Fabrine; Faria, B F; Chantier, Thibaut; Breton, Michelyne; Pellet, Johann; Davoust, Nathalie; Mangeot, Philippe; Chaboud, Annie; Pénin, François; Jacob, Yves; Vidalain, Pierre‐Olivier; Vidal, Marc; André, Patrice; Rabourdin–Combe, Chantal; Lotteau, Vincent

doi:10.1038/msb.2008.66

Cited by 347 publications

(303 citation statements)

References 70 publications

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“…Numerous protein-protein interactions have been reported for NS5A, including viral (61)(62)(63)(64)(65) or host cell proteins (reviewed in Ref. 66). The unfolded nature of D2 and D3 could contribute to their hublike character for protein interactions with high specificities and low affinities (67).…”

Section: Discussionmentioning

confidence: 99%

Domain 3 of NS5A Protein from the Hepatitis C Virus Has Intrinsic α-Helical Propensity and Is a Substrate of Cyclophilin A

Verdegem

Badillo

Wieruszeski

et al. 2011

Journal of Biological Chemistry

101

106

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Nonstructural protein 5A (NS5A) is essential for hepatitis C virus (HCV) replication and constitutes an attractive target for antiviral drug development. Although structural data for its in-plane membrane anchor and domain D1 are available, the structure of domains 2 (D2) and 3 (D3) remain poorly defined. We report here a comparative molecular characterization of the NS5A-D3 domains of the HCV JFH-1 (genotype 2a) and Con1 (genotype 1b) strains. Combining gel filtration, CD, and NMR spectroscopy analyses, we show that NS5A-D3 is natively unfolded. However, NS5A-D3 domains from both JFH-1 and Con1 strains exhibit a propensity to partially fold into an ␣-helix. NMR analysis identifies two putative ␣-helices, for which a molecular model could be obtained. The amphipathic nature of the first helix and its conservation in all genotypes suggest that it might correspond to a molecular recognition element and, as such, promote the interaction with relevant biological partner(s). Because mutations conferring resistance to cyclophilin inhibitors have been mapped into NS5A-D3, we also investigated the functional interaction between NS5A-D3 and cyclophilin A (CypA). CypA indeed interacts with NS5A-D3, and this interaction is completely abolished by cyclosporin A. NMR heteronuclear exchange experiments demonstrate that CypA has in vitro peptidyl-prolyl cis/trans-isomerase activity toward some, but not all, of the peptidyl-prolyl bonds in NS5A-D3. These studies lead to novel insights into the structural features of NS5A-D3 and its relationships with CypA. Hepatitis C virus (HCV),3 a small enveloped virus from the Flaviviridae family, is a major cause of chronic liver disease that may lead to steatosis, liver cirrhosis, and hepatocellular carcinoma. Given about 180 million chronically infected individuals worldwide, HCV is an important health challenge (1). Current therapy is based on a combination of pegylated interferon-␣ and ribavirin but is not fully satisfying because numerous patients are not responding or suffer from serious side effects caused by this treatment. The development of new drugs to treat HCV infections requires a better understanding of the structural and functional features of the viral proteins and their relationships with host cell factors. The HCV genome (ϳ9.6 kb) encodes for a single polyprotein precursor (ϳ3,000 aa) that is co-and post-translationally processed by cellular and viral proteases to yield 10 mature proteins (2, 3). They are classified into structural proteins (Core, E1, and E2), which constitute the viral particle, and nonstructural proteins, of which two, p7 and nonstructural protein 2 (NS2), are required for virus assembly. The remainder of the nonstructural proteins (NS3, NS4A, NS4B, NS5A, and NS5B) are involved in HCV RNA replication (reviewed in Refs. 2 and 3).Cyclophilins are host cell factors that in addition to viral proteins, are equally essential for HCV replication. The human genome encodes up to 16 different cyclophilins (4) that, despite differences in their tissue distributio...

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Section: Discussionmentioning

confidence: 99%

Domain 3 of NS5A Protein from the Hepatitis C Virus Has Intrinsic α-Helical Propensity and Is a Substrate of Cyclophilin A

Verdegem

Badillo

Wieruszeski

et al. 2011

Journal of Biological Chemistry

101

106

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“…Experiments involving pull-down methods have been applied more generally in the determination of proteome-wide interaction networks. 76 A brief summary of progress towards understanding the interaction networks during HCV infection will be discussed in the Proteomics approaches section of this article.…”

Section: Identifying Host-virus Interactions Biochemical Methodsmentioning

confidence: 99%

Host–virus interactions during hepatitis C virus infection: a complex and dynamic molecular biosystem

2010

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The hepatitis C virus (HCV) is a global health issue with no vaccine available and limited clinical treatment options. Like other obligate parasites, HCV requires host cellular components of an infected individual to propagate. These host-virus interactions during HCV infection are complex and dynamic and involve the hijacking of host cell environments, enzymes and pathways. Understanding this unique molecular biosystem has the potential to yield new and exciting strategies for therapeutic intervention. Advances in genomics and proteomics have opened up new possibilities for the rapid measurement of global changes at the transcriptional and translational levels during infection. However, these techniques only yield snapshots of host-virus interactions during HCV infection. Other new methods that involve the imaging of biomolecular interactions during HCV infection are required to identify key interactions that may be transient and dynamic. Herein we highlight systems biology based strategies that have helped to identify key host-virus interactions during HCV replication and infection. Novel biophysical tools are also highlighted for identification and visualization of activities and interactions between HCV and its host hepatocyte. As some of these methods mature, we expect them to pave the way forward for further exploration of this complex biosystem and elucidation of mechanisms for HCV pathogenesis and carcinogenesis.

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“…The genetic heterogeneity of HCV gives an adaptive advantage as the simultaneous presence of multiple genomic variants allows rapid selection of mutants that better adapt to environmental changes (for example resistance to drugs or the immune response); this genetic heterogeneity is the basis of chronic infection, and is probably involved in the phenomena of evasion of the immune response and in the limited efficacy of treatment [56][57][58][59] . The HCV replication cycle occurs in the cytoplasm, and can be summarized as follows: (1) entry into the host cell and release of viral genomic RNA into the cytoplasm; (2) translation of RNA, processing of the viral polyprotein and formation of a replication complex associated with intracellular membrane; (3) using positive RNA for the synthesis of an intermediate negative RNA for the production of new positive RNA molecules with different destination; and (4) release of viral progeny into circulation from infected cells.…”

Section: Treatment and Svr -What Is The Real Purpose Of Antiviral Thementioning

confidence: 99%

Chronic hepatitis C: This and the new era of treatment

Bertino

Ardiri

Proiti

et al. 2016

WJH

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Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects. Core tip: This review analyzes the current therapies for chronic hepatitis C and the future challenges of the research. So it tries to give an update on the research of hepatitis C virus (HCV) infection, providing a critical view of the emerging therapies and their impact on the future management of HCV infection. Since novel TOPIC HIGHLIGHT Chronic hepatitis C: This and the new era of treatment2016 Hepatitis C Virus: Global view treatments for HCV infection are highly efficacious but costly, priority should be given to patients with advanced hepatic fibrosis, which is a disease that cannot be deferred. INTRODUCTIONThe hepatitis C virus (HCV), identified in the 70s but cloned in 1989, is a single-stranded RNA virus belonging to the family Flaviviridae.HCV is the main cause of progressive liver diseases and a public health problem worldwide. It is estimated that approximately 150-180 million people in the world are living with chronic hepatitis [1,2] , 350 million of whom die each year from liver damage associated with the infection [3] . About 80% of people infected with HCV develop chronic hepatitis, of which 20%-40% will develop liver cirrhosis or hepatocellular carcinoma (HCC) 20-30 years after infection.As a consequence, chronic HCV infection is the major reason of liver transplantation in developed countries [4][5][6][7] . According to the Global Burden Disease Study in Europe, the death rate for viral hepatitis is significantly higher than that for human immunodeficiency virus (HIV) and acquired immune deficiency syndrome; in particular in 2010, the number of deaths from viral hepatitis have been ten times bigger than that attributed to HIV. It is reasonable to think that this difference is due to the lack of effective therapies for HCV until a few years ago [8] .HCV is also one of the main causes of death [9] . The virus causes both liver damage and extra-hepatic manifestations, many of these syndromes are associated with the ability of HCV to replicate in peripheral blood mononuclear cells (PBMCs); an example is the mixed cryoglobulinemia, which is by far the most common extrahepatic disease closely connected with the infection.Recently it was shown that antiviral treatment is associated with improved renal and cardiovascular outcomes in patients with cryoglobulinemia [4,6,10,11] . Newly approved oral anti-HCV drugs are very safe and effective, but unfortunately their cost will force to choose a priority of treatment. The intent should therefore be to identify and treat patients with a higher risk of morbidity and mortality due to HCV.The availability of these new oral treatments can definitely heal patients and ...

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Hepatitis C virus infection protein network

Cited by 347 publications

References 70 publications

Domain 3 of NS5A Protein from the Hepatitis C Virus Has Intrinsic α-Helical Propensity and Is a Substrate of Cyclophilin A

Domain 3 of NS5A Protein from the Hepatitis C Virus Has Intrinsic α-Helical Propensity and Is a Substrate of Cyclophilin A

Host–virus interactions during hepatitis C virus infection: a complex and dynamic molecular biosystem

Chronic hepatitis C: This and the new era of treatment

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