Hepatitis C virus core protein: Not just a nucleocapsid building block, but an immunity and inflammation modulator

Coevolution occurs between viruses and their hosts. The hosts need to evolve means to eliminate pathogenic virus infections, and the viruses, for their own survival and multiplication, have to develop mechanisms to escape clearance by hosts. Hepatitis C virus (HCV) of Flaviviridae is a pathogen which infects human liver and causes hepatitis, a condition of liver inflammation. Unlike most of the other flaviviruses, HCV has an excellent ability to evade host immunity to establish chronic infection. The persistent liver infection leads to chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), as well as extrahepatic HCV-related diseases. HCV genomic RNA only expresses 10 proteins, many of which bear functions, in addition to those involved in HCV life cycle, for assisting the virus to develop its persistency. HCV core protein is a structural protein which encapsulates HCV genomic RNA and assembles into nucleocapsids. The core protein is also found to exert functions to affect host inflammation and immune responses by altering a variety of host pathways. This paper reviews the studies regarding the HCV core protein-induced alterations of host immunity and inflammatory responses, as well as the involvements of the HCV core protein in pro- and anti-inflammatory cytokine stimulations, host cellular transcription, lipid metabolism, cell apoptosis, cell proliferations, immune cell differentiations, oxidative stress, and hepatocyte steatosis, which leads to liver fibrosis, cirrhosis, and HCC. Implications of roles played by the HCV core protein in therapeutic resistance are also discussed.