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

Authors: Sainz, B., Jr; Barretto, N.; Martin, D. N.; Hiraga, N.; Imamura, M; Hussain, S.; Marsh, K. A.; Yu, X.; Chayama, K; Alrefai, W. A.; Uprichard, S. L.
Article Title: Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor
Abstract: Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With approximately 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.
Journal Title: Nature medicine
Volume: 18
Issue: 2
ISSN: 1546-170X; 1078-8956
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 281
End Page: 285
Language: eng
Notes: LR: 20130626; GR: R01 AI070827/AI/NIAID NIH HHS/United States; GR: R01 AI070827-01S1/AI/NIAID NIH HHS/United States; GR: R01 AI070827-03/AI/NIAID NIH HHS/United States; GR: R01-AI070827/AI/NIAID NIH HHS/United States; GR: R03 AI085226/AI/NIAID NIH HHS/United States; GR: R03 AI085226-01/AI/NIAID NIH HHS/United States; GR: R03-AI085226/AI/NIAID NIH HHS/United States; GR: UL1 RR029879/RR/NCRR NIH HHS/United States; GR: UL1RR029879/RR/NCRR NIH HHS/United States; JID: 9502015; 0 (Anticholesteremic Agents); 0 (Azetidines); 0 (Membrane Transport Proteins); 0 (Npc1l1 protein, mouse); 163222-33-1 (ezetimibe); 57-88-5 (Cholesterol); CIN: J Hepatol. 2012 Jul;57(1):215-7. PMID: 22387665; CIN: Nat Rev Gastroenterol Hepatol. 2012 Mar;9(3):124. PMID: 22330814; NIHMS334578; OID: NLM: NIHMS334578; OID: NLM: PMC3530957; 2011/03/16 [received]; 2011/10/25 [accepted]; 2012/01/08 [aheadofprint]; epublish