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Identification of the Niemann-Pick C1–like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ∼170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by... Full description

Journal Title: Nature medicine 2012-01-08, Vol.18 (2), p.281-285
Main Author: Sainz, Jr, Bruno
Other Authors: Barretto, Naina , Martin, Danyelle N , Hiraga, Nobuhiko , Imamura, Michio , Hussain, Snawar , Marsh, Katherine A , Yu, Xuemei , Chayama, Kazuaki , Alrefai, Waddah A , Uprichard, Susan L
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
Link: https://www.ncbi.nlm.nih.gov/pubmed/22231557
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title: Identification of the Niemann-Pick C1–like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor
format: Article
creator:
  • Sainz, Jr, Bruno
  • Barretto, Naina
  • Martin, Danyelle N
  • Hiraga, Nobuhiko
  • Imamura, Michio
  • Hussain, Snawar
  • Marsh, Katherine A
  • Yu, Xuemei
  • Chayama, Kazuaki
  • Alrefai, Waddah A
  • Uprichard, Susan L
subjects:
  • Animals
  • Anticholesteremic Agents - pharmacology
  • Antiviral agents
  • Article
  • Azetidines - pharmacology
  • Care and treatment
  • Cholesterol
  • Cholesterol - metabolism
  • digestive system diseases
  • Dosage and administration
  • Drug therapy
  • Ezetimibe
  • Hepacivirus - drug effects
  • Hepacivirus - physiology
  • Hepatitis
  • Hepatitis C - metabolism
  • Hepatitis C - virology
  • Hepatitis C virus
  • Human immunodeficiency virus
  • Humans
  • Liver diseases
  • Male
  • Membrane Transport Proteins - metabolism
  • Mice
  • Neurons
  • Patient outcomes
  • Protease inhibitors
  • Risk factors
  • virus diseases
  • Virus Internalization - drug effects
ispartof: Nature medicine, 2012-01-08, Vol.18 (2), p.281-285
description: Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ∼170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by the US Food and Drug Administration (FDA), optimal HCV therapy, analogous to HIV therapy, will probably require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a potential multifaceted target for antiviral intervention; however, to date, FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection, as silencing or antibody-mediated blocking of NPC1L1 impairs cell culture-derived HCV (HCVcc) infection initiation. In addition, the clinically available FDA-approved NPC1L1 antagonist ezetimibe potently blocks HCV uptake in vitro via a virion cholesterol-dependent step before virion-cell membrane fusion. Moreover, ezetimibe inhibits infection by all major HCV genotypes in vitro and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor but also discovered a new antiviral target and potential therapeutic agent.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


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titleIdentification of the Niemann-Pick C1–like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor
creatorSainz, Jr, Bruno ; Barretto, Naina ; Martin, Danyelle N ; Hiraga, Nobuhiko ; Imamura, Michio ; Hussain, Snawar ; Marsh, Katherine A ; Yu, Xuemei ; Chayama, Kazuaki ; Alrefai, Waddah A ; Uprichard, Susan L
creatorcontribSainz, Jr, Bruno ; Barretto, Naina ; Martin, Danyelle N ; Hiraga, Nobuhiko ; Imamura, Michio ; Hussain, Snawar ; Marsh, Katherine A ; Yu, Xuemei ; Chayama, Kazuaki ; Alrefai, Waddah A ; Uprichard, Susan L
descriptionHepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ∼170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by the US Food and Drug Administration (FDA), optimal HCV therapy, analogous to HIV therapy, will probably require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a potential multifaceted target for antiviral intervention; however, to date, FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection, as silencing or antibody-mediated blocking of NPC1L1 impairs cell culture-derived HCV (HCVcc) infection initiation. In addition, the clinically available FDA-approved NPC1L1 antagonist ezetimibe potently blocks HCV uptake in vitro via a virion cholesterol-dependent step before virion-cell membrane fusion. Moreover, ezetimibe inhibits infection by all major HCV genotypes in vitro and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor but also discovered a new antiviral target and potential therapeutic agent.
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subjectAnimals ; Anticholesteremic Agents - pharmacology ; Antiviral agents ; Article ; Azetidines - pharmacology ; Care and treatment ; Cholesterol ; Cholesterol - metabolism ; digestive system diseases ; Dosage and administration ; Drug therapy ; Ezetimibe ; Hepacivirus - drug effects ; Hepacivirus - physiology ; Hepatitis ; Hepatitis C - metabolism ; Hepatitis C - virology ; Hepatitis C virus ; Human immunodeficiency virus ; Humans ; Liver diseases ; Male ; Membrane Transport Proteins - metabolism ; Mice ; Neurons ; Patient outcomes ; Protease inhibitors ; Risk factors ; virus diseases ; Virus Internalization - drug effects
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descriptionHepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ∼170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by the US Food and Drug Administration (FDA), optimal HCV therapy, analogous to HIV therapy, will probably require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a potential multifaceted target for antiviral intervention; however, to date, FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection, as silencing or antibody-mediated blocking of NPC1L1 impairs cell culture-derived HCV (HCVcc) infection initiation. In addition, the clinically available FDA-approved NPC1L1 antagonist ezetimibe potently blocks HCV uptake in vitro via a virion cholesterol-dependent step before virion-cell membrane fusion. Moreover, ezetimibe inhibits infection by all major HCV genotypes in vitro and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor but also discovered a new antiviral target and potential therapeutic agent.
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titleIdentification of the Niemann-Pick C1–like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor
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abstractHepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ∼170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by the US Food and Drug Administration (FDA), optimal HCV therapy, analogous to HIV therapy, will probably require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a potential multifaceted target for antiviral intervention; however, to date, FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection, as silencing or antibody-mediated blocking of NPC1L1 impairs cell culture-derived HCV (HCVcc) infection initiation. In addition, the clinically available FDA-approved NPC1L1 antagonist ezetimibe potently blocks HCV uptake in vitro via a virion cholesterol-dependent step before virion-cell membrane fusion. Moreover, ezetimibe inhibits infection by all major HCV genotypes in vitro and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor but also discovered a new antiviral target and potential therapeutic agent.
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