Hepatitis C virus (HCV), the major causative agent of non-A and non-B hepatitis, is estimated to infect 2% of the world's population (Alter M J, 1997). Viral infection persists in approximately 80% of infected individuals, causing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (Pawlotsky J M, 2004). No vaccine against HCV is currently available and therapeutic approaches remain limited (Houghton M, et al., 2005).
The HCV core protein, which is derived from the N terminus of the viral polyprotein, is not only a component of the nucleocapsid but also has properties that enable it to modulate a number of cellular processes. Several studies suggest that the HCV core protein can regulate cell signal transduction, including MAPK-, JAK-STAT-, NF-κB-, AP-1-and SRE-associated pathways, resulting in the regulation of apoptosis and the suppression of host immunity (Lai M M, et al., 2000; McLauchlan J, 2000). Several studies suggest that the expression of the core protein affects mitochondrial function and lipid metabolism (Moriya K, et al., 2001; Okuda M, et al., 2002). Furthermore, transgenic mice that express the HCV-core protein exhibit certain features of human infection, such as steatosis, insulin resistance and ultimately cancer (Moriya K, et al., 1997; Moriya K, et al., 1998). These results suggest that the core protein might play an important role in the pathogenesis and carcinogenesis of an HCV infection.
The amino acid sequence of the core protein is well conserved among different HCV isolates and genotypes compared to other HCV proteins (Suzuki R, et al., 2005). A signal sequence in its C-terminal region facilitates channeling of the nascent HCV polyprotein to the endoplasmic reticulum (ER) membrane and is the substrate for processing by two host proteases (Kopp M, et al., 2010). After cleavage by signal peptidase (SP), a 23-kDa core protein (191aa, p23) is released and is further processed by signal peptide peptidase (SPP), an integral membrane protease, to yield a 21-kDa core protein (177aa, p21) (Hussy P, et al., 1996). The cleavage by SPP promotes the release of core protein from the ER membrane, and then it is trafficked to lipid droplets, which are reported to be the site of HCV particle assembly (McLauchlan J, et al., 2002; Okamoto K, et al., 2008). The expression of a 16-kDa core protein (p16) was found in HCV infected patients, indicating that p16 might be related to chronic HCV infection, but the exact C-terminus of the p16 core protein has not been determined (Yeh C T, et al., 2000). Recently several groups have found that the substitution of amino acid (aa) 70 and/or 91 in the core region of HCV genotype 1b (HCV-1b) is associated with a poor response to pegylated interferon and ribavirin as well as an important predictor of hepatocarcinogenesis (Akuta N, et al., 2010; Akuta N, et al., 2012). Frameshift proteins and internal initiation minicore proteins have also been reported although their functions remain unclear (Eng F J, et al., 2009; Walewski J L, et al., 2001).
The development of an cell culture system for HCV (HCVcc) is a major breakthrough in the field (Heller T, 2005; Wakita T, et al., 2005; Zhong J, 2005). As well HCV infection in human, persistent infection can be established in HCVcc in vitro (Zhong J, et al., 2006), which facilitates our understanding of the details of the pathophysiology of persistent HCV infection. To study the possible function of the core protein in persistent HCV infection, its expression was detected during the establishment of HCVcc persistent infection and three sizes (~19 kDa, ~21 kDa and ~24 kDa) of core proteins were identified. Moreover, the three core proteins can all be encapsidated into HCV virions. Of the three resulting core proteins, the p21 core protein was the mature form of the HCV core protein. The p19 core protein might be the cleavage product of the p21 core protein, and the p24 core protein was the phophorylated form of p21. The phosphorylation of the core protein may play an important role in the establishment of persistent HCVcc infection.
The Identification of Three Sizes of Core Proteins during the Establishment of Persistent Hepatitis C Virus Infection in vitro
- Received Date: 12 December 2012
- Accepted Date: 08 March 2013
Abstract: Similar to Hepatitis C virus (HCV) infection in humans, HCVcc infection can also result in persistent and chronic infection. The core protein is a variable protein and exists in several sizes. Some sizes of core proteins have been reported to be related to chronic HCV infection. To study the possible role of the core protein in persistent HCV infection, a persistent HCVcc infection was established, and the expression of the core protein was analysed over the course of the infection. The results show that there are three sizes of core proteins (p24, p21 and p19) expressed during the establishment of persistent HCVcc infection. Of these, the p21 core protein is the mature form of the HCV core protein. The p24 core protein is the phosphorylated form of p21. The p19 core protein appears to be a functional by-product generated during the course of infection. These three core proteins are all localized in the cytoplasm and can be encapsidated into the HCV virion. The appearance of the p19 and p24 core proteins might be related to acute HCVcc infection and chronic infection respectively and may play an important role in the pathology of a HCV infection.