New research shows that Niemann-Pick C1–like 1 (NPC1L1) cholesterol uptake receptor is an HCV cell entry factor that functions after binding, at or before fusion. Together with the facts that NPC1L1 is a cellular cholesterol receptor, the HCV particle is enriched in cholesterol, and relative dependence on NPC1L1 is correlated with HCV particle cholesterol levels, supports and expands on previous reports suggesting that virion cholesterol is involved in HCV cell entry. Whether NPC1L1 directly interacts with HCV or indirectly participates in HCV entry by removing virion-associated cholesterol to perhaps reveal protected viral glycoprotein binding sites or confer a required conformational change remains to be determined. As NPC1L1 is expressed only on human and primate hepatocytes, this discovery additionally highlights NPC1L1 as a potential HCV tropism determinant, which may facilitate the future development of animal models of HCV infection.
Identification of the Niemann-Pick C1–like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. Nature Medicine 08 January 2012 doi:10.1038/nm.2581
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.