Induction and evasion of innate antiviral responses by hepatitis C virus

Abstract

Persistent hepatitis C virus infection is associated with progressive hepatic fibrosis and liver cancer. Acute infection evokes several distinct innate immune responses, but these are partially or completely countered by the virus. Hepatitis C virus proteins serve dual functions in replication and immune evasion, acting to disrupt cellular signaling pathways leading to interferon synthesis, subvert Jak-STAT signaling to limit expression of interferon-stimulated genes, and block antiviral activities of interferon-stimulated genes. The net effect is a multilayered evasion of innate immunity, which negatively influences the subsequent development of antigen-specific adaptive immunity, thereby contributing to virus persistence and resistance to therapy.

FIGURE 1.

Organization of the positive-sense RNA genome of HCV. Genomic RNA contains a single large open reading frame flanked by 5′- and 3′-untranslated RNA segments. The open reading frame encodes a polyprotein of >3000 amino acids that undergoes processing by cellular and viral proteases to produce 10 mature proteins. The core (C) and envelope proteins E1 and E2 are structural components of the infectious virus particle, whereas the remaining proteins are nonstructural (NS) and required for RNA replication (NS3–NS5B) or particle assembly and egress from the cell (p7 and NS2). Major viral protease activities include NS2, which cleaves in cis at the NS2-NS3 junction, and NS3/4A, a noncovalent complex of the N-terminal domain of NS3 and an accessory peptide sequence from NS4A that directs cleavage at the sites indicated by the red arrowheads and also targets the cellular signaling proteins MAVS and TRIF for proteolysis.

FIGURE 2.

RIG-I and TLR3 sensing of viral RNAs induces IFN-β synthesis. Two distinct signaling pathways, one initiated by the recognition of 5′-triphosphate-containing cytosolic viral RNAs by the DExD box helicase RIG-I (left) and the other by TLR3 recognition of viral dsRNA >40–50 bp within the lumen of vesicles in an early endosomal compartment (right), lead to phosphorylation of IRF3, activation of NF-κB, and induction of IFN-β transcription. Both pathways are disrupted by expression of the viral NS3/4A protease, which cleaves the adaptor proteins MAVS and TRIF, respectively. See text for details. In addition to those proteins shown, roles have been suggested for MEKK1, FADD, and RIP in RIG-I signaling leading to IFN-β synthesis. TM, transmembrane domain; PI3K, phosphatidylinositol 3-kinase; IKK, IκB kinase; MITA, mediator of IRF3 activation.

FIGURE 3.

Suppression of IFN-induced Jak-STAT signaling in hepatitis C. Type I (IFN-α/β) and III (IFN-λ) IFNs initiate signaling by binding to distinct heterodimeric receptors on the plasma membrane but then signal through a common pathway involving Tyk-2 and Jak-1 phosphorylation of STAT1 and STAT2 and subsequent recruitment of IRF9 to form the transcription factor ISGF3, which stimulates transcription of ISGs under the control of IFN-stimulated response elements. The HCV core protein may confound these responses by interacting directly with STAT1, whereas endoplasmic reticulum stress within infected cells may induce PP2A activity that acts indirectly through PRMT1 and PIAS to suppress signaling. Type I IFN signaling may also be impeded by induction of USP18 that interacts directly with the IFNAR2 subunit of the IFNAR. See text for details. ISRE, IFN-stimulated response element.