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Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor
Bruno Sainz1, Naina Barretto, Danyelle N Martin
1Department of Medicine, University of Illinois-Chicago, Chicago, Illinois, USA.
Abstract:
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.
Insights
Researchers identified the Niemann-Pick C1-like 1 (NPC1L1) cholesterol receptor as a crucial factor for Hepatitis C virus (HCV) entry. The drug ezetimibe, an NPC1L1 antagonist, effectively blocks HCV infection, offering a new therapeutic strategy for this liver disease.
Area of Science:
- Hepatology
- Virology
- Molecular Biology
Background:
- Hepatitis C virus (HCV) infection affects millions globally, necessitating improved treatments beyond current interferon-based therapies.
- Existing treatments for HCV have limitations, including toxic side effects and variable efficacy, highlighting the need for novel antiviral agents.
- While protease inhibitors are available, combination therapies targeting multiple stages of the viral lifecycle, like entry, are essential for optimal HCV treatment.
Purpose of the Study:
- To identify novel cellular factors involved in Hepatitis C virus (HCV) entry into host cells.
- To investigate the role of the Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor in HCV infection.
- To evaluate the therapeutic potential of targeting NPC1L1 for HCV antiviral intervention.
Main Methods:
- Silencing and antibody-mediated blocking of the NPC1L1 receptor to assess its necessity for HCV infection.
- In vitro and in vivo studies using the FDA-approved NPC1L1 antagonist ezetimibe to evaluate its efficacy in blocking HCV uptake and infection.
- Testing ezetimibe's inhibitory effect across major HCV genotypes and in a mouse model with human liver grafts.
Main Results:
- NPC1L1 expression was found to be essential for the initiation of cell culture-derived HCV (HCVcc) infection.
- Ezetimibe demonstrated potent inhibition of HCV uptake in vitro, acting before virion-cell membrane fusion.
- Ezetimibe effectively inhibited infection by all tested major HCV genotypes in vitro and delayed HCV genotype 1b infection in vivo.
Conclusions:
- The cellular cholesterol uptake receptor NPC1L1 is identified as a critical host factor for Hepatitis C virus entry.
- Ezetimibe, a clinically approved NPC1L1 antagonist, represents a promising new therapeutic agent for blocking HCV infection.
- Targeting NPC1L1 offers a novel strategy for developing effective antiviral therapies against Hepatitis C virus.
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