DOI: 10.1002/hep.22555. Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel

Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel

10.1002/hep.22555

Crossref journal-article

Ovid Technologies (Wolters Kluwer Health)

Hepatology (276)

Abstract

Abstract The hepatitis C virus (HCV) p7 protein plays a critical role during particle formation in cell culture and is required for virus replication in chimpanzees. The discovery that it displayed cation channel activity in vitro led to its classification within the “viroporin” family of virus-coded ion channel proteins, which includes the influenza A virus (IAV) M2 protein. Like M2, p7 was proposed as a potential target for much needed new HCV therapies, and this was supported by our finding that the M2 inhibitor, amantadine, blocked its activity in vitro . Since then, further compounds have been shown to inhibit p7 function but the relationship between inhibitory effects in vitro and efficacy against infectious virus is controversial. Here, we have sought to validate multiple p7 inhibitor compounds using a parallel approach combining the HCV infectious culture system and a rapid throughput in vitro assay for p7 function. We identify a genotype-dependent and subtype-dependent sensitivity of HCV to p7 inhibitors, in which results in cell culture largely mirror the sensitivity of recombinant protein in vitro ; thus building separate sensitivity profiles for different p7 sequences. Inhibition of virus entry also occurred, suggesting that p7 may be a virion component. Second site effects on both cellular and viral processes were identified for several compounds in addition to their efficacy against p7 in vitro . Nevertheless, for some compounds antiviral effects were specific to a block of ion channel function. Conclusion: These data validate p7 inhibitors as prototype therapies for chronic HCV disease. (Hepatology 2008;48:1779-1790.)

Bibliography

Griffin, S., StGelais, C., Owsianka, A. M., Patel, A. H., Rowlands, D., & Harris, M. (2008). Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel. Hepatology, 48(6), 1779â1790.

Authors 6

Stephen Griffin (first)
Corine StGelais (additional)
Ania M. Owsianka (additional)
Arvind H. Patel (additional)
David Rowlands (additional)
Mark Harris (additional)

References 39 Referenced 107

10.1053/j.gastro.2007.02.037 / Gastroenterology / Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. by Sarrazin (2007)
10.1016/j.antiviral.2003.08.017 / Antiviral Res / Membrane association of hepatitis C virus nonstructural proteins and identification of the membrane alteration that harbors the viral replication complex. by Moradpour (2003)
10.1073/pnas.0508531102 / Proc Natl Acad Sci U S A / Hepatitis C virus protease NS34A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. by Li (2005)
10.1099/vir.0.80204-0 / J Gen Virol / Hepatitis C virus NS5A: tales of a promiscuous protein. by Macdonald (2004)
10.1126/science.1114016 / Science / Complete replication of hepatitis C virus in cell culture. by Lindenbach (2005)
10.1038/nm1268 / Nat Med / Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. by Wakita (2005)
10.1073/pnas.0503596102 / Proc Natl Acad Sci U S A / Robust hepatitis C virus infection in vitro. by Zhong (2005)
10.1074/jbc.M602434200 / J Biol Chem / Evidence for the formation of a heptameric ion channel complex by the hepatitis C virus p7 protein in vitro. by Clarke (2006)
10.1016/S0014-5793(03)01453-4 / FEBS Lett / Cationselective ion channels formed by p7 of hepatitis C virus are blocked by hexamethylene amiloride. by Premkumar (2004)
10.1073/pnas.1031527100 / Proc Natl Acad Sci U S A / The hepatitis C virus p7 protein forms an ion channel that is inhibited by longalkylchain iminosugar derivatives. by Pavlovic (2003)
10.1016/S0014-5793(02)03851-6 / FEBS Lett / The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine. by Griffin (2003)
10.1128/JVI.76.8.3720-3730.2002 / J Virol / Subcellular localization and topology of the p7 polypeptide of hepatitis C virus. by CarrereKremer (2002)
10.1128/jvi.68.10.6215-6222.1994 / J Virol / Two hepatitis C virus glycoprotein E2 products with different C termini. by Mizushima (1994)
10.1128/jvi.68.8.5063-5073.1994 / J Virol / Processing in the hepatitis C virus E2NS2 region: identification of p7 and two distinct E2specific products with different C termini. by Lin (1994)
10.1099/vir.0.19634-0 / J Gen Virol / A conserved basic loop in hepatitis C virus p7 protein is required for amantadinesensitive ion channel activity in mammalian cells but is dispensable for localization to mitochondria. by Griffin (2004)
10.1073/pnas.1834545100 / Proc Natl Acad Sci U S A / The p7 polypeptide of hepatitis C virus is critical for infectivity and contains functionally important genotypespecific sequences. by Sakai (2003)
10.1128/JVI.00690-07 / J Virol / Hepatitis C virus p7 and NS2 proteins are essential for production of infectious virus. by Jones (2007)
10.1371/journal.ppat.0030103 / PLoS Pathog / Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions. by Steinmann (2007)
10.1099/vir.0.82049-0 / J Gen Virol / Hepatitis C virus p7 protein is localized in the endoplasmic reticulum when it is encoded by a replicationcompetent genome. by Haqshenas (2007)
10.1128/JVI.79.24.15525-15536.2005 / J Virol / Signal peptide cleavage and internal targeting signals direct the hepatitis C virus p7 protein to distinct intracellular membranes. by Griffin (2005)
10.1016/j.jhep.2004.05.019 / J Hepatol / Evaluation of amantadine in chronic hepatitis C: a metaanalysis. by Deltenre (2004)
10.1016/j.antiviral.2007.05.001 / Antiviral Res / Inhibition of hepatitis C virus p7 membrane channels in a liposomebased assay system. by StGelais (2007)
10.1002/j.1460-2075.1985.tb04038.x / EMBO J / The molecular basis of the specific antiinfluenza action of amantadine. by Hay (1985)
10.1002/hep.21686 / HEPATOLOGY / Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus. by Steinmann (2007)
10.1073/pnas.0504877103 / Proc Natl Acad Sci U S A / Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimeras. by Pietschmann (2006)
10.1099/vir.0.81334-0 / J Gen Virol / Development and characterization of a transientreplication assay for the genotype 2a hepatitis C virus subgenomic replicon. by TargettAdams (2005)
10.1006/viro.1998.9092 / Virology / Transcripts of a chimeric cDNA clone of hepatitis C virus genotype 1b are infectious in vivo. by Yanagi (1998)
10.1099/vir.0.81553-0 / J Gen Virol / Tagging of NS5A expressed from a functional hepatitis C virus replicon. by McCormick (2006)
10.1084/jem.20021756 / J Exp Med / Infectious hepatitis C virus pseudoparticles containing functional E1-E2 envelope protein complexes. by Bartosch (2003)
10.1093/emboj/cdf414 / EMBO J / Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. by McLauchlan (2002)
10.1099/0022-1317-82-8-1877 / J Gen Virol / Functional analysis of hepatitis C virus E2 glycoproteins and viruslike particles reveals structural dissimilarities between different forms of E2. by Owsianka (2001)
10.1074/jbc.M210900200 / J Biol Chem / The hepatitis C virus nonstructural NS5A protein inhibits activating protein1 function by perturbing rasERK pathway signaling. by Macdonald (2003)
10.1128/JVI.75.8.3527-3536.2001 / J Virol / Antiviral effect of Nbutyldeoxynojirimycin against bovine viral diarrhea virus correlates with misfolding of E2 envelope proteins and impairment of their association into E1-E2 heterodimers. by BranzaNichita (2001)
10.1128/jvi.70.6.4131-4135.1996 / J Virol / Processing in the pestivirus E2NS2 region: identification of proteins p7 and E2p7. by Elbers (1996)
10.1128/JVI.75.19.8987-8998.2001 / J Virol / Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus. by Durantel (2001)
10.1073/pnas.94.21.11301 / Proc Natl Acad Sci U S A / A functionally defined model for the M2 proton channel of influenza A virus suggests a mechanism for its ion selectivity. by Pinto (1997)
10.1021/bi0028441 / Biochemistry / Protonation of histidine and histidinetryptophan interaction in the activation of the M2 ion channel from influenza a virus. by Okada (2001)
10.1016/j.jhep.2005.11.038 / J Hepatol / Amantadine triple therapy for nonresponder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI). by Maynard (2006)
10.1023/A:1013703013053 / Dig Dis Sci / Amantadines viral kinetics in chronic hepatitis C infection. by Chan (2002)

Dates

Type	When
Created	17 years, 1 month ago (July 28, 2008, 11:13 a.m.)
Deposited	9 months ago (Dec. 1, 2024, 8:37 a.m.)
Indexed	2 months, 1 week ago (June 21, 2025, 12:48 a.m.)
Issued	16 years, 9 months ago (Dec. 1, 2008)
Published	16 years, 9 months ago (Dec. 1, 2008)
Published Print	16 years, 9 months ago (Dec. 1, 2008)

Funders 0

None

BibTeX

@article{Griffin_2008, title={Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel}, volume={48}, ISSN={0270-9139}, url={http://dx.doi.org/10.1002/hep.22555}, DOI={10.1002/hep.22555}, number={6}, journal={Hepatology}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Griffin, Stephen and StGelais, Corine and Owsianka, Ania M. and Patel, Arvind H. and Rowlands, David and Harris, Mark}, year={2008}, month=dec, pages={1779–1790} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        6,
        21
      ]
    ],
    "date-time": "2025-06-21T04:48:07Z",
    "timestamp": 1750481287468,
    "version": "3.30.0"
  },
  "reference-count": 39,
  "publisher": "Ovid Technologies (Wolters Kluwer Health)",
  "issue": "6",
  "license": [
    {
      "start": {
        "date-parts": [
          [
            2015,
            9,
            1
          ]
        ],
        "date-time": "2015-09-01T00:00:00Z",
        "timestamp": 1441065600000
      },
      "content-version": "tdm",
      "delay-in-days": 2465,
      "URL": "http://doi.wiley.com/10.1002/tdm_license_1.1"
    }
  ],
  "content-domain": {
    "domain": [
      "lww.com",
      "ovid.com"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2008,
        12
      ]
    ]
  },
  "abstract": "<jats:sec>\n            <jats:title>Abstract</jats:title>\n            <jats:p>\n                                 <jats:bold>The hepatitis C virus (HCV) p7 protein plays a critical role during particle formation in cell culture and is required for virus replication in chimpanzees. The discovery that it displayed cation channel activity</jats:bold>\n                                 <jats:bold>\n                                    in vitro\n                                 </jats:bold>\n                                 <jats:bold>led to its classification within the \u201cviroporin\u201d family of virus-coded ion channel proteins, which includes the influenza A virus (IAV) M2 protein. Like M2, p7 was proposed as a potential target for much needed new HCV therapies, and this was supported by our finding that the M2 inhibitor, amantadine, blocked its activity</jats:bold>\n                                 <jats:bold>\n                                    in vitro\n                                 </jats:bold>\n                                 <jats:bold>. Since then, further compounds have been shown to inhibit p7 function but the relationship between inhibitory effects</jats:bold>\n                                 <jats:bold>\n                                    in vitro\n                                 </jats:bold>\n                                 <jats:bold>and efficacy against infectious virus is controversial. Here, we have sought to validate multiple p7 inhibitor compounds using a parallel approach combining the HCV infectious culture system and a rapid throughput</jats:bold>\n                                 <jats:bold>\n                                    in vitro\n                                 </jats:bold>\n                                 <jats:bold>assay for p7 function. We identify a genotype-dependent and subtype-dependent sensitivity of HCV to p7 inhibitors, in which results in cell culture largely mirror the sensitivity of recombinant protein</jats:bold>\n                                 <jats:bold>\n                                    in vitro\n                                 </jats:bold>\n                                 <jats:bold>; thus building separate sensitivity profiles for different p7 sequences. Inhibition of virus entry also occurred, suggesting that p7 may be a virion component. Second site effects on both cellular and viral processes were identified for several compounds in addition to their efficacy against p7</jats:bold>\n                                 <jats:bold>\n                                    in vitro\n                                 </jats:bold>\n                                 <jats:bold>. Nevertheless, for some compounds antiviral effects were specific to a block of ion channel function.</jats:bold>\n                                 <jats:bold>\n                                    Conclusion:\n                                 </jats:bold>\n                                 <jats:bold>These data validate p7 inhibitors as prototype therapies for chronic HCV disease. (Hepatology 2008;48:1779-1790.)</jats:bold>\n                              </jats:p>\n          </jats:sec>",
  "DOI": "10.1002/hep.22555",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2008,
        7,
        28
      ]
    ],
    "date-time": "2008-07-28T15:13:13Z",
    "timestamp": 1217257993000
  },
  "page": "1779-1790",
  "update-policy": "http://dx.doi.org/10.1097/lww.0000000000001000",
  "source": "Crossref",
  "is-referenced-by-count": 107,
  "title": "Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel",
  "prefix": "10.1097",
  "volume": "48",
  "author": [
    {
      "given": "Stephen",
      "family": "Griffin",
      "sequence": "first",
      "affiliation": []
    },
    {
      "given": "Corine",
      "family": "StGelais",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Ania M.",
      "family": "Owsianka",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Arvind H.",
      "family": "Patel",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "David",
      "family": "Rowlands",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Mark",
      "family": "Harris",
      "sequence": "additional",
      "affiliation": []
    }
  ],
  "member": "276",
  "reference": [
    {
      "key": "R2-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "1767",
      "DOI": "10.1053/j.gastro.2007.02.037",
      "article-title": "Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir.",
      "volume": "132",
      "author": "Sarrazin",
      "year": "2007",
      "journal-title": "Gastroenterology"
    },
    {
      "key": "R3-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "103",
      "DOI": "10.1016/j.antiviral.2003.08.017",
      "article-title": "Membrane association of hepatitis C virus nonstructural proteins and identification of the membrane alteration that harbors the viral replication complex.",
      "volume": "60",
      "author": "Moradpour",
      "year": "2003",
      "journal-title": "Antiviral Res"
    },
    {
      "key": "R4-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "17717",
      "DOI": "10.1073/pnas.0508531102",
      "article-title": "Hepatitis C virus protease NS34A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity.",
      "volume": "102",
      "author": "Li",
      "year": "2005",
      "journal-title": "Proc Natl Acad Sci U S A"
    },
    {
      "key": "R5-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "2485",
      "DOI": "10.1099/vir.0.80204-0",
      "article-title": "Hepatitis C virus NS5A: tales of a promiscuous protein.",
      "volume": "85",
      "author": "Macdonald",
      "year": "2004",
      "journal-title": "J Gen Virol"
    },
    {
      "key": "R6-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "623",
      "DOI": "10.1126/science.1114016",
      "article-title": "Complete replication of hepatitis C virus in cell culture.",
      "volume": "309",
      "author": "Lindenbach",
      "year": "2005",
      "journal-title": "Science"
    },
    {
      "key": "R7-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "791",
      "DOI": "10.1038/nm1268",
      "article-title": "Production of infectious hepatitis C virus in tissue culture from a cloned viral genome.",
      "volume": "11",
      "author": "Wakita",
      "year": "2005",
      "journal-title": "Nat Med"
    },
    {
      "key": "R8-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "9294",
      "DOI": "10.1073/pnas.0503596102",
      "article-title": "Robust hepatitis C virus infection in vitro.",
      "volume": "102",
      "author": "Zhong",
      "year": "2005",
      "journal-title": "Proc Natl Acad Sci U S A"
    },
    {
      "key": "R9-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "37057",
      "DOI": "10.1074/jbc.M602434200",
      "article-title": "Evidence for the formation of a heptameric ion channel complex by the hepatitis C virus p7 protein in vitro.",
      "volume": "281",
      "author": "Clarke",
      "year": "2006",
      "journal-title": "J Biol Chem"
    },
    {
      "key": "R10-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "99",
      "DOI": "10.1016/S0014-5793(03)01453-4",
      "article-title": "Cationselective ion channels formed by p7 of hepatitis C virus are blocked by hexamethylene amiloride.",
      "volume": "557",
      "author": "Premkumar",
      "year": "2004",
      "journal-title": "FEBS Lett"
    },
    {
      "key": "R11-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "6104",
      "DOI": "10.1073/pnas.1031527100",
      "article-title": "The hepatitis C virus p7 protein forms an ion channel that is inhibited by longalkylchain iminosugar derivatives.",
      "volume": "100",
      "author": "Pavlovic",
      "year": "2003",
      "journal-title": "Proc Natl Acad Sci U S A"
    },
    {
      "key": "R12-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "34",
      "DOI": "10.1016/S0014-5793(02)03851-6",
      "article-title": "The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine.",
      "volume": "535",
      "author": "Griffin",
      "year": "2003",
      "journal-title": "FEBS Lett"
    },
    {
      "key": "R13-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "3720",
      "DOI": "10.1128/JVI.76.8.3720-3730.2002",
      "article-title": "Subcellular localization and topology of the p7 polypeptide of hepatitis C virus.",
      "volume": "76",
      "author": "CarrereKremer",
      "year": "2002",
      "journal-title": "J Virol"
    },
    {
      "key": "R14-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "6215",
      "DOI": "10.1128/jvi.68.10.6215-6222.1994",
      "article-title": "Two hepatitis C virus glycoprotein E2 products with different C termini.",
      "volume": "68",
      "author": "Mizushima",
      "year": "1994",
      "journal-title": "J Virol"
    },
    {
      "key": "R15-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "5063",
      "DOI": "10.1128/jvi.68.8.5063-5073.1994",
      "article-title": "Processing in the hepatitis C virus E2NS2 region: identification of p7 and two distinct E2specific products with different C termini.",
      "volume": "68",
      "author": "Lin",
      "year": "1994",
      "journal-title": "J Virol"
    },
    {
      "key": "R16-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "451",
      "DOI": "10.1099/vir.0.19634-0",
      "article-title": "A conserved basic loop in hepatitis C virus p7 protein is required for amantadinesensitive ion channel activity in mammalian cells but is dispensable for localization to mitochondria.",
      "volume": "85",
      "author": "Griffin",
      "year": "2004",
      "journal-title": "J Gen Virol"
    },
    {
      "key": "R17-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "11646",
      "DOI": "10.1073/pnas.1834545100",
      "article-title": "The p7 polypeptide of hepatitis C virus is critical for infectivity and contains functionally important genotypespecific sequences.",
      "volume": "100",
      "author": "Sakai",
      "year": "2003",
      "journal-title": "Proc Natl Acad Sci U S A"
    },
    {
      "key": "R18-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "8374",
      "DOI": "10.1128/JVI.00690-07",
      "article-title": "Hepatitis C virus p7 and NS2 proteins are essential for production of infectious virus.",
      "volume": "81",
      "author": "Jones",
      "year": "2007",
      "journal-title": "J Virol"
    },
    {
      "key": "R19-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "e103",
      "DOI": "10.1371/journal.ppat.0030103",
      "article-title": "Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions.",
      "volume": "3",
      "author": "Steinmann",
      "year": "2007",
      "journal-title": "PLoS Pathog"
    },
    {
      "key": "R20-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "134",
      "DOI": "10.1099/vir.0.82049-0",
      "article-title": "Hepatitis C virus p7 protein is localized in the endoplasmic reticulum when it is encoded by a replicationcompetent genome.",
      "volume": "88",
      "author": "Haqshenas",
      "year": "2007",
      "journal-title": "J Gen Virol"
    },
    {
      "key": "R21-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "15525",
      "DOI": "10.1128/JVI.79.24.15525-15536.2005",
      "article-title": "Signal peptide cleavage and internal targeting signals direct the hepatitis C virus p7 protein to distinct intracellular membranes.",
      "volume": "79",
      "author": "Griffin",
      "year": "2005",
      "journal-title": "J Virol"
    },
    {
      "key": "R22-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "462",
      "DOI": "10.1016/j.jhep.2004.05.019",
      "article-title": "Evaluation of amantadine in chronic hepatitis C: a metaanalysis.",
      "volume": "41",
      "author": "Deltenre",
      "year": "2004",
      "journal-title": "J Hepatol"
    },
    {
      "key": "R23-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "48",
      "DOI": "10.1016/j.antiviral.2007.05.001",
      "article-title": "Inhibition of hepatitis C virus p7 membrane channels in a liposomebased assay system.",
      "volume": "76",
      "author": "StGelais",
      "year": "2007",
      "journal-title": "Antiviral Res"
    },
    {
      "key": "R24-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "3021",
      "DOI": "10.1002/j.1460-2075.1985.tb04038.x",
      "article-title": "The molecular basis of the specific antiinfluenza action of amantadine.",
      "volume": "4",
      "author": "Hay",
      "year": "1985",
      "journal-title": "EMBO J"
    },
    {
      "key": "R25-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "330",
      "DOI": "10.1002/hep.21686",
      "article-title": "Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus.",
      "volume": "46",
      "author": "Steinmann",
      "year": "2007",
      "journal-title": "HEPATOLOGY"
    },
    {
      "key": "R26-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "7408",
      "DOI": "10.1073/pnas.0504877103",
      "article-title": "Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimeras.",
      "volume": "103",
      "author": "Pietschmann",
      "year": "2006",
      "journal-title": "Proc Natl Acad Sci U S A"
    },
    {
      "key": "R27-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "3075",
      "DOI": "10.1099/vir.0.81334-0",
      "article-title": "Development and characterization of a transientreplication assay for the genotype 2a hepatitis C virus subgenomic replicon.",
      "volume": "86",
      "author": "TargettAdams",
      "year": "2005",
      "journal-title": "J Gen Virol"
    },
    {
      "key": "R28-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "161",
      "DOI": "10.1006/viro.1998.9092",
      "article-title": "Transcripts of a chimeric cDNA clone of hepatitis C virus genotype 1b are infectious in vivo.",
      "volume": "244",
      "author": "Yanagi",
      "year": "1998",
      "journal-title": "Virology"
    },
    {
      "key": "R29-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "635",
      "DOI": "10.1099/vir.0.81553-0",
      "article-title": "Tagging of NS5A expressed from a functional hepatitis C virus replicon.",
      "volume": "87",
      "author": "McCormick",
      "year": "2006",
      "journal-title": "J Gen Virol"
    },
    {
      "key": "R30-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "633",
      "DOI": "10.1084/jem.20021756",
      "article-title": "Infectious hepatitis C virus pseudoparticles containing functional E1-E2 envelope protein complexes.",
      "volume": "197",
      "author": "Bartosch",
      "year": "2003",
      "journal-title": "J Exp Med"
    },
    {
      "key": "R31-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "3980",
      "DOI": "10.1093/emboj/cdf414",
      "article-title": "Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets.",
      "volume": "21",
      "author": "McLauchlan",
      "year": "2002",
      "journal-title": "EMBO J"
    },
    {
      "key": "R32-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "1877",
      "DOI": "10.1099/0022-1317-82-8-1877",
      "article-title": "Functional analysis of hepatitis C virus E2 glycoproteins and viruslike particles reveals structural dissimilarities between different forms of E2.",
      "volume": "82",
      "author": "Owsianka",
      "year": "2001",
      "journal-title": "J Gen Virol"
    },
    {
      "key": "R33-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "17775",
      "DOI": "10.1074/jbc.M210900200",
      "article-title": "The hepatitis C virus nonstructural NS5A protein inhibits activating protein1 function by perturbing rasERK pathway signaling.",
      "volume": "278",
      "author": "Macdonald",
      "year": "2003",
      "journal-title": "J Biol Chem"
    },
    {
      "key": "R34-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "3527",
      "DOI": "10.1128/JVI.75.8.3527-3536.2001",
      "article-title": "Antiviral effect of Nbutyldeoxynojirimycin against bovine viral diarrhea virus correlates with misfolding of E2 envelope proteins and impairment of their association into E1-E2 heterodimers.",
      "volume": "75",
      "author": "BranzaNichita",
      "year": "2001",
      "journal-title": "J Virol"
    },
    {
      "key": "R35-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "4131",
      "DOI": "10.1128/jvi.70.6.4131-4135.1996",
      "article-title": "Processing in the pestivirus E2NS2 region: identification of proteins p7 and E2p7.",
      "volume": "70",
      "author": "Elbers",
      "year": "1996",
      "journal-title": "J Virol"
    },
    {
      "key": "R36-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "8987",
      "DOI": "10.1128/JVI.75.19.8987-8998.2001",
      "article-title": "Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus.",
      "volume": "75",
      "author": "Durantel",
      "year": "2001",
      "journal-title": "J Virol"
    },
    {
      "key": "R37-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "11301",
      "DOI": "10.1073/pnas.94.21.11301",
      "article-title": "A functionally defined model for the M2 proton channel of influenza A virus suggests a mechanism for its ion selectivity.",
      "volume": "94",
      "author": "Pinto",
      "year": "1997",
      "journal-title": "Proc Natl Acad Sci U S A"
    },
    {
      "key": "R38-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "6053",
      "DOI": "10.1021/bi0028441",
      "article-title": "Protonation of histidine and histidinetryptophan interaction in the activation of the M2 ion channel from influenza a virus.",
      "volume": "40",
      "author": "Okada",
      "year": "2001",
      "journal-title": "Biochemistry"
    },
    {
      "key": "R39-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "484",
      "DOI": "10.1016/j.jhep.2005.11.038",
      "article-title": "Amantadine triple therapy for nonresponder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI).",
      "volume": "44",
      "author": "Maynard",
      "year": "2006",
      "journal-title": "J Hepatol"
    },
    {
      "key": "R40-8-20241201",
      "doi-asserted-by": "crossref",
      "first-page": "438",
      "DOI": "10.1023/A:1013703013053",
      "article-title": "Amantadines viral kinetics in chronic hepatitis C infection.",
      "volume": "47",
      "author": "Chan",
      "year": "2002",
      "journal-title": "Dig Dis Sci"
    }
  ],
  "container-title": "Hepatology",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fhep.22555",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "text-mining"
    },
    {
      "URL": "https://journals.lww.com/01515467-200812000-00008",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2024,
        12,
        1
      ]
    ],
    "date-time": "2024-12-01T13:37:06Z",
    "timestamp": 1733060226000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://journals.lww.com/01515467-200812000-00008"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2008,
        12
      ]
    ]
  },
  "references-count": 39,
  "journal-issue": {
    "issue": "6",
    "published-print": {
      "date-parts": [
        [
          2008
        ]
      ]
    }
  },
  "URL": "http://dx.doi.org/10.1002/hep.22555",
  "relation": {},
  "ISSN": [
    "0270-9139"
  ],
  "subject": [],
  "published": {
    "date-parts": [
      [
        2008,
        12
      ]
    ]
  }
}