Topic
NS5B
About: NS5B is a research topic. Over the lifetime, 1314 publications have been published within this topic receiving 59534 citations.
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TL;DR: Hepatitis C virus induces autophagosomes via a Class III PI3K-independent pathway and uses autophile membranes as sites for its RNA replication, indicating that the silencing of the expression of LC3 or Atg7, two protein factors critical for the formation of autphagosomes, suppresses the replication of HCV RNA.
152 citations
TL;DR: A model in which the incorporation of the HCV polymerase into the RC depends on its interaction with a cellular chaperone protein and in which cyclosporine inhibits HCV replication by blocking this critical interaction and the PPIase activity of CyPA is proposed.
Abstract: Replication of hepatitis C virus (HCV) RNA occurs on intracellular membranes, and the replication complex (RC) contains viral RNA, nonstructural proteins, and cellular cofactors. We previously demonstrated that cyclophilin A (CyPA) is an essential cofactor for HCV infection and the intracellular target of cyclosporine's anti-HCV effect. Here we investigate the mechanism by which CyPA facilitates HCV replication. Cyclosporine treatment specifically blocked the incorporation of NS5B into the RC without affecting either the total protein level or the membrane association of the protein. Other nonstructural proteins or viral RNAs in the RC were not affected. NS5B from the cyclosporine-resistant replicon was resistant to this disruption of RC incorporation. We also isolated membrane fractions from both naive and HCV-positive cells and found that CyPA is recruited into membrane fractions in HCV-replicating cells via an interaction with RC-associated NS5B, which is sensitive to cyclosporine treatment. Finally, we introduced point mutations in the prolyl-peptidyl isomerase (PPIase) motif of CyPA and demonstrated a critical role of this motif in HCV replication in cDNA rescue experiments. We propose a model in which the incorporation of the HCV polymerase into the RC depends on its interaction with a cellular chaperone protein and in which cyclosporine inhibits HCV replication by blocking this critical interaction and the PPIase activity of CyPA. Our results provide a mechanism of action for the cyclosporine-mediated inhibition of HCV and identify a critical role of CyPA's PPIase activity in the proper assembly and function of the HCV RC.
152 citations
TL;DR: The apo-polymerase structure provides unprecedented insights into potential non-nucleoside inhibitor binding sites located between palm and thumb near motif E, which is unique to RNA polymerases and reverse transcriptases.
151 citations
TL;DR: The results of this study provide a basis for the optimization and subsequent development of members of the Flavonoid family as specific HCV antivirals.
150 citations
TL;DR: It is concluded that a benign course of HCV infection may be the consequence of the effective activation of T‐helper lymphocytes.
148 citations