Inhibition of Tumor Necrosis Factor (TNF-α)-mediated Apoptosis by Hepatitis C Virus Core Protein

Abstract

Hepatitis C virus (HCV) putative core protein has displayed many intriguing biological properties. Since tumor necrosis factor (TNF) plays an important role in controlling viral infection, in this study the effect of the core protein was investigated on the TNF-␣ induced apoptosis of human breast carcinoma cells (MCF7). HCV core protein when expressed inhibited TNF-␣-induced apoptotic cell death unlike the control MCF7 cells, as determined by cell viability and DNA fragmentation analysis. Additionally, HCV core protein blocked the TNF-induced proteolytic cleavage of the death substrate poly(ADP-ribose) polymerase from its native 116-kDa protein to the characteristic 85-kDa polypeptide. Results from this study suggest that the HCV core protein plays a role in the inhibition of TNF-␣-mediated cell death. Thus, the ability of core protein to inhibit the TNF-mediated apoptotic signaling pathway may provide a selective advantage for HCV replication, allowing for evasion of host antiviral defense mechanisms. Hepatitis C virus (HCV)1 is an important cause of morbidity and mortality worldwide, causing a spectrum of liver disease ranging from an asymptomatic carrier state to end-stage liver disease. The most important feature of persistent HCV infection is the development of chronic hepatitis in half of the infected individuals and the potential for disease progression to hepatocellular carcinoma (1). Unfortunately, a number of important issues related to HCV-mediated disease progression is unknown at this time. An HCV genome contains a linear, positive-strand RNA molecule of ϳ9,500 nucleotides encoding a single polyprotein precursor of ϳ3,000 amino acids (2). The polyprotein is cleaved by both host and viral proteases (3, 4) to generate three putative structural proteins (core, E1, and E2) and at least six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The genomic region encoding the putative core protein is located between amino acids 1-191. HCV core protein may be the fundamental unit for the encapsidation of genomic RNA to facilitate virus morphogenesis.However, in vitro studies suggest that the HCV core protein has many additional biological properties. The core protein transactivates the human c-myc proto-oncogene and unrelated viral promoters and suppresses c-fos, p53, and human immunodeficiency virus type 1 long terminal repeat promoter activities (5-7). HCV core protein transforms primary rat embryo fibroblasts in association with a cooperative oncogene to a tumorigenic phenotype (8), interacts with the lymphotoxin-␤ receptor to possibly modulate immune function (9), and associates with apolipoprotein II for a potential role on lipid metabolism (10). A recent study (11) suggests that missense mutations in the clustering variable region of the hydrophilic domain (residues 39 -76) of the core gene may be involved in the pathogenesis of chronic HCV infection during hepatocellular carcinogenesis.Viral infections may often induce an apoptotic response as a defense mechanism in host cells, and many vir...

Mycoplasma fermentans inhibits tumor necrosis factor α-induced apoptosis in the human myelomonocytic U937 cell line

“…Only a few papers have been published regarding inhibition of TNFa-induced apoptosis by Chlamydia pneumonia 23,24 and Hepatitis C Virus. 25 These support the hypothesis 26 that parasite bacteria might use a mechanism to prevent host cell apoptosis, in order to promote their survival and replication.…”

Genetic mechanisms of hepatocarcinogenesis

“…The ®nding of a low percentage of p53 mutations in HCV infected patients with HCC (Pontisso et al, 1998) is consistent with the possibility that in HCV (and HBV) infection, one or more viral proteins may inactivate wild type p53. The constitutive activation of the mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway by HCV core expressing HepG2 cells in the presence of a tumor promoter , combined with observations that HCV core inhibits Fas and tumor necrosis factor (TNF-a)-mediated apoptosis in selected cell lines (Marusawa et al, 1999;Ray et al, 1998), suggests additional mechanisms of cell survival that may contribute importantly to hepatocarcinogenesis. These events suggest that one or more HCV gene products may contribute to early changes in the development of HCC, although it is not clear whether the alterations observed in vitro and/or in tissue culture cells accurately re¯ect in vivo mechanisms.…”

Activation of the interferon-inducible protein kinase PKR by Hepatocellular carcinoma derived-Hepatitis C virus core protein

“…HCV core has been described as being associated with lymphotoxin-b receptor, TNF-receptor 1, apolipoprotein AII, hnRNP and a bZIP transcription factor (Barba et al, 1997;Chen et al, 1997;Hsieh et al, 1998;Sabile et al, 1999). Evidence exists that HCV core may have an e ect upon cell transformation (Jin et al, 2000) and apoptosis (Marusawa et al, 1999;Ray et al, 1996Ray et al, , 1998Ruggieri et al, 1997); however, the biological consequences of core ectopic expression depend on the levels of expression achieved, the cell type utilized and the cellular environment (Honda et al, 2000;Zhu et al, 1998).…”