Emerging concepts in immunity to hepatitis C virus infection
Hugo R. Rosen
Hugo R. Rosen
Published October 1, 2013
Citation Information: J Clin Invest. 2013;123(10):4121-4130. https://doi.org/10.1172/JCI67714.
View: Text | PDF
Review

Emerging concepts in immunity to hepatitis C virus infection

Abstract

Since the discovery of hepatitis C virus (HCV) by molecular cloning almost a quarter of a century ago, unprecedented at the time because the virus had never been grown in cell culture or detected serologically, there have been impressive strides in many facets of our understanding of the natural history of the disease, the viral life cycle, the pathogenesis, and antiviral therapy. It is apparent that the virus has developed multiple strategies to evade immune surveillance and eradication. This Review covers what we currently understand of the temporal and spatial immunological changes within the human innate and adaptive host immune responses that ultimately determine the outcomes of HCV infection.

Authors

Hugo R. Rosen

×

Figure 1

Hepatocyte innate immune responses.

Options: View larger image (or click on image) Download as PowerPoint
Hepatocyte innate immune responses. (A) LDL receptors (LDLRs) on the bas...
(A) LDL receptors (LDLRs) on the basolateral hepatocyte surface, SR-BI, CD81, and tight-junction proteins CLDN-1 (claudin-1) and OCLN (occludin) are essential for HCV uptake (9). Intracellular HCV recognition occurs through dsRNA sensors such as RIG-I and TLR-3. MAMs function as the central scaffold that coordinates MAVS-dependent signaling of the RIG-I pathway between mitochondria and peroxisomes (21). MAVS interacts with the essential adapter protein TRAF3 to further recruit downstream kinases; activation of the kinases IKK-ε and TANK-binding kinase 1 (TBK1), which phosphorylate the transcription factors IRF-3 and IRF-7 (19), and binding to NF-κB lead to the induction of antiviral and immunomodulatory genes, including types I and III IFNs, as well as chemokines and proinflammatory cytokines that function in parallel with IFNs to mediate the response to HCV (147). (B) Binding of type I IFNs to the IFN-α/β receptors (IFN-αR1 and -2) and type III IFNs (IFN-λ) to the heterodimeric IL-28Ra/IL-10Rβ receptor (24) results in activation of the JAK/STAT pathway, conferring stable association with IRF-9. The resulting IFN-stimulated gene factor 3 (ISGF3) transcription factor complex localizes to the hepatocyte nucleus, where it binds to the ISREs within the promoter/enhancer region of hundreds of ISGs (147). Autocrine and paracrine signaling in neighboring cells results in anti-HCV amplification loops (including IRF-7, which binds to IFN promoters). HCV core protein subverts immunity by the induction of suppressors of cytokine signaling (SOCS1/SOCS3) and by impairing the binding of ISGF3 to nuclear IFN ISREs (19). See text for details.