Barriers of hepatitis C virus interspecies transmission

Abstract

Hepatitis C virus (HCV) is a major causative agent of severe liver disease including fibrosis, cirrhosis and liver cancer. Therapy has improved over the years, but continues to be associated with adverse side effects and variable success rates. Furthermore, a vaccine protecting against HCV infection remains elusive. Development of more effective intervention measures has been delayed by the lack of a suitable animal model. Naturally, HCV infects only humans and chimpanzees. The determinants of this limited host range are poorly understood in part due to difficulties of studying HCV in cell culture. Some progress has been made elucidating the barriers for the HCV lifecycle in non-permissive species which will help in the future to construct animal models for HCV infection, immunity and pathogenesis.

Fig. 1

Blocks in HCV species tropism. Mouse hepatocytes support HCV replication cycle incompletely. CLDN1, claudin1; EGFR, epidermal growth factor receptor; EphA2, ephrin receptor A2; GAG, Glycosaminoglycans; LDLR, low-density lipoprotein receptor; NPC1L1, Niemann-Pick C1-Like 1; OCLN, occludin; SCARB1, scavenger receptor class B member 1. (+) supported, (−) blocked step in the HCV lifecycle in murine cells.

Fig. 2

Innate immune response to HCV infection. Ch; chimpanzee, dsRNA, double-stranded RNA; ER, endoplasmatic reticulum; hu, human; IFN, interferon; IFNAR, interferon-alpha receptor; IL, interleukin; IRF, interferon regulatory factor; JAK, Janus kinase; ms, mouse; MAVS, mitochondrial associated antiviral signaling protein; MDA5, melanoma-differentiation-associated gene 5; PKR, protein kinase R; rh, rhesus macaque; RIG-I, retinoic-acid-inducible gene I; ssRNA, single-stranded RNA; STAT1, signal transducer and activator of transcription protein-1; STAT2, signal transducer and activator of transcription protein-2; STING, stimulator of interferon genes; TLR, toll-like receptor; TRIF, TIR-domain-containing adapter-inducing interferonβ; TYK, tyrosine kinase. Inlet: sequence alignment of the NS3–4a cleavage motif within MAVS from different permissive and non-permissive species.