Hepatitis A and hepatitis C viruses: divergent infection outcomes marked by similarities in induction and evasion of interferon responses.
Hepatitis A and hepatitis C viruses (HAV and HCV) are both positive-strand ribonucleic acid (RNA) viruses with hepatotropic lifestyles. Despite several important differences, they share many biological and molecular features and similar genome replication schemes. Despite this, HAV infections are usually effectively controlled by the host with elimination of the virus, whereas HCV most often is able to establish lifelong persistent infection. The mechanisms underlying this difference are unknown. The cellular helicases RIG-I and MDA5, and Toll-like receptor 3, are pattern recognition receptors that sense virus-derived RNAs within hepatocytes in the liver. Activation of these receptors leads to their interaction with specific adaptor proteins, mitochondrial antiviral signaling protein (MAVS) and TIR-domain-containing adapter-inducing interferon-β (TRIF), respectively, which engage downstream kinases to activate two crucial transcription factors, nuclear factor kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). This results in the induction of interferons (IFNs) and IFN-stimulated genes that ultimately establish an antiviral state. These signaling pathways are central to host antiviral defense and thus frequent targets for viral interference. Both HAV and HCV express proteases that target signal transduction through these pathways and that block the induction of IFNs upon sensing of viral RNA by these receptors. An understanding of the differences and similarities in the early innate immune responses to these infections is likely to provide important insights into the mechanism underlying the long-term persistence of HCV.
Department of Medicine, The University of North Carolina, Chapel Hill, NC, USA.
Lin
L
Qu
Stanley M
SM
Lemon
D056704:Adaptive Immunity / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology; D016174:Hepacivirus / Q000276:immunology / Q000502:physiology*; D006506:Hepatitis A / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D030041:Hepatitis A virus / Q000276:immunology / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D007113:Immunity, Innate / Q000502:physiology; D000072640:Interferon-Induced Helicase, IFIH1; D008099:Liver / Q000276:immunology / Q000503:physiopathology; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000502:physiology; D014158:Transcription, Genetic; D014775:Virus Activation / Q000502:physiology*; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C505371:MAVS protein, human; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1