Restoration of the activated Rig-I pathway in hepatitis C virus (HCV) replicon cells by HCV protease, polymerase, and NS5A inhibitors in vitro at clinically relevant concentrations.
نویسندگان
چکیده
Development of persistent hepatitis C virus (HCV) infection may be mediated by HCV NS3 · 4A protease-dependent inhibition of host innate immunity. When double-stranded RNA (dsRNA) is detected in virus-infected cells, host innate immunity mounts an antiviral response by upregulating production of type I interferons (α/β interferon [IFN-α/β]); HCV counters by cleaving the IFN-β stimulator 1 (IPS-1) adaptor protein, decreasing synthesis of IFN-α/β. We evaluated HCV protease (telaprevir, boceprevir, and TMC435350), polymerase (HCV-796 and VX-222), and NS5A (BMS-790052) inhibitors for the ability to restore IPS-1-mediated Rig-I signaling by measuring Sendai virus-induced IFN-β promoter activation in HCV replicon cells after various exposure durations. All direct-acting HCV antivirals tested restored mitochondrial localization of IPS-1 and rescued Sendai virus-induced IRF3 signaling after 7 days by inhibiting HCV replication, thereby reducing the abundance of HCV NS3 · 4A protease. With 4-day treatment, HCV protease inhibitors, but not polymerase inhibitors, restored mitochondrial localization of IPS-1 and rescued IFN-β promoter activation in the presence of equivalent levels of NS3 protein in protease or polymerase inhibitor-treated cells. The concentrations of HCV protease and polymerase inhibitors needed to rescue IRF3-mediated signaling in vitro were in the range of those observed in vivo in the plasma of treated HCV patients. These findings suggest that (i) HCV protease, polymerase, and NS5A inhibitors can restore virus-induced IRF3 signaling by inhibiting viral replication, thereby reducing NS3 protease levels, and (ii) HCV protease inhibitors can restore innate immunity by directly inhibiting NS3 protease-mediated cleavage of IPS-1 at clinically achievable concentrations.
منابع مشابه
A Cell-Based Assay for RNA Synthesis by the HCV Polymerase Reveals New Insights on Mechanism of Polymerase Inhibitors and Modulation by NS5A
RNA synthesis by the genotype 1b hepatitis C virus (HCV) polymerase (NS5B) transiently expressed in Human embryonic kidney 293T cells or liver hepatocytes was found to robustly stimulate RIG-I-dependent luciferase production from the interferon β promoter in the absence of exogenously provided ligand. This cell-based assay, henceforth named the 5BR assay, could be used to examine HCV polymerase...
متن کاملThe Full Length Hepatitis C Virus Polyprotein and Interactions with the Interferon-Beta Signalling Pathways in vitro
Background: Hepatitis C is a global health problem. The exact mechanisms by which hepatitis C virus (HCV) can evade the host immune system have become controversial. Whether HCV polyproteins modulate IFN signalling pathways or HCV proteins are responsible for such a property is the subject of interest. Therefore, an efficient baculovirus delivery system was developed to introduce the whole geno...
متن کاملIn vitro activity and resistance profile of samatasvir, a novel NS5A replication inhibitor of hepatitis C virus.
The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is a clinically validated target for drugs designed to treat chronic HCV infection. This study evaluated the in vitro activity, selectivity, and resistance profile of a novel anti-HCV compound, samatasvir (IDX719), alone and in combination with other antiviral agents. Samatasvir was effective and selective against infectious HCV and re...
متن کاملNS5A inhibitors: a new breakthrough for the treatment of chronic hepatitis C.
The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferonalpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral age...
متن کاملJTK-853, a novel non-nucleoside hepatitis C virus polymerase inhibitor, demonstrates a high genetic barrier to resistance in vitro.
JTK-853 is a novel, non-nucleoside, palm site-binding hepatitis C virus (HCV) polymerase inhibitor that has demonstrated antiviral activity in HCV-infected patients during 3 days of treatment. To estimate the genetic barrier of JTK-853 to resistance in vitro, colony formation assays were conducted using HCV replicon cells (genotypes 1a and 1b). The colony formation assays revealed that the numb...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Antimicrobial agents and chemotherapy
دوره 57 9 شماره
صفحات -
تاریخ انتشار 2013