Interaction between CD81 and claudin 1 facilitates viral uptake by clathrin-mediated endocytosis (Meertens et al., 2006 Farquhar et al., 2012). The virus enters host cells (hepatocytes) by initial binding to low-affinity receptors the LDL receptor and glycosaminoglycans on the heparan sulphate proteoglycans, followed by binding to scavenger receptor class B member 1 and stepwise translocation to post-binding co-receptors the tetraspanin CD81 and tight junction proteins claudin 1 and occludin (Pileri et al., 1998 Agnello et al., 1999 Scarselli et al., 2002 Evans et al., 2007 Ploss et al., 2009 Jiang et al., 2012 Lindenbach and Rice, 2013). The virus particles are unusual in that they are associated with low-density lipoproteins (LDLs) and very low-density lipoproteins (VLDLs) to form the lipoviroparticles (Andre et al., 2002). HCV is a single-stranded, positive-sense RNA Hepacivirus (a genus of the family Flaviviridae) with a 9.6 kb genome (Figure вЂ‹ (Figure1) 1) (Scheel and Rice, 2013 Simmonds, 2013). It is therefore important to understand how HCV interacts with the host UPR, taking into consideration the genotypes and the various experimental systems used to dissect this virus-host interaction. For viruses that establish persistent infection it is even more important to be able to adapt to chronic ER stress, otherwise diseases will ensue. Thus UPR is far from being a homeostatic response in terms of virus infection. On the other hand, UPR is recruited by the host anti-viral machinery to help eliminating virus infection (Clavarino et al., 2012). UPR has also been frequently manipulated by a number of viruses to aid in infection and to attenuate anti-viral response (Isler et al., 2005 Smith et al., 2006 Yu et al., 2006 Liu et al., 2009 Jheng et al., 2010 Ambrose and Mackenzie, 2011 Pena and Harris, 2011 Burnett et al., 2012 Galindo et al., 2012 Qian et al., 2012 Rathore et al., 2013 Stahl et al., 2013). Recently the unfolded protein response (UPR), a host homeostatic response to endoplasmic reticulum (ER) stress, has emerged to be a novel mechanism involved in a number of human diseases including that caused by virus infections (Dimcheff et al., 2003 Favreau et al., 2009 Wang and Kaufman, 2012). Understanding how the virus interacts with the host is key to answer these questions. How the virus establishes persistence and causes diseases is still far from clear.

The disease usually manifests itself as chronic hepatitis, which can progress into fibrosis, cirrhosis and eventually into hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) infection produces a clinically important disease affecting around 3% of the world population (Thomas, 2013).

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