Viral infection of mammalian cells rapidly triggers intracellular signalling events leading to interferon alpha/beta production and a cellular antiviral state. This 'host response' is our first line of immune defence against infection as it imposes several barriers to viral replication and spread. Hepatitis C virus (HCV) evades the host response through a complex combination of processes that include signalling interference, effector modulation and continual viral genetic variation. These evasion strategies support persistent infection and the spread of HCV. Defining the molecular mechanisms by which HCV regulates the host response is of crucial importance and may reveal targets for novel therapeutic strategies.

The non-structural 5A (NS5A) protein of hepatitis C virus (HCV) has been the subject of intensive research over the last decade. It is generally accepted that NS5A is a pleiotropic protein with key roles in both viral RNA replication and modulation of the physiology of the host cell. Our understanding of the role of NS5A in the virus life cycle has been hampered by the lack of a robust in vitro system for the study of HCV replication, although the recent development of the subgenomic replicon has at least allowed us to begin to dissect the involvement of NS5A in the process of viral RNA replication. Early studies into the effects of NS5A on cell physiology relied on expression of NS5A either alone or in the context of other non-structural proteins; the advent of the replicon system has allowed the extrapolation of these studies to a more physiologically relevant cellular context. Despite recent progress, this field is controversial, and there is much work to be accomplished before we fully understand the many functions of this protein. In this article, the current state of our knowledge of NS5A, discussing in detail its direct involvement in virus replication, together with its role in modulating the cellular environment to favour virus replication and persistence, are reviewed. The effects of NS5A on interferon signalling, and the regulation of cell growth and apoptosis are highlighted, demonstrating that this protein is indeed of critical importance for HCV and is worthy of further investigation.

Hepatitis C virus infection represents a major problem of public health with around 350 millions of chronically infected individuals worldwide. The frequent evolution towards severe liver disease and cancer are the main features of HCV chronic infection. Antiviral therapies, mainly based on the combination of IFN and ribavirin can only assure a long term eradication of the virus in less than half of treated patients. The mechanisms underlying HCV pathogenesis and persistence in the host are still largely unknown and the efforts made by researchers in the understanding the viral biology have been hampered by the absence of a reliable in vitro and in vivo system reproducing HCV infection. The present review will mainly focus on viral pathogenetic mechanisms based on the interaction of HCV proteins (especially core, NS3 and NS5A) with host cellular signaling transduction pathways regulating cell growth and viability and on the strategies developed by the virus to persist in the host and escape to antiviral therapy. Past and recent data obtained in this field with different experimental approaches will be discussed.

Abnormal accumulation of fat in the liver (steatosis) is commonly observed in hepatitis C virus (HCV) infection, and the severity of steatosis has been well correlated with the degree of hepatic fibrosis. In patients with chronic HCV infection, steatosis may occur in conjunction with other metabolic risk factors such as insulin resistance and the metabolic syndrome. This was observed primarily in patients infected with non-genotype 3 virus. Otherwise, in HCV-infected patients, especially those infected with genotype 3a, reductions in total cholesterol as well as high-density lipoprotein and low-density lipoprotein cholesterol are observed compared with matched controls, and the normalization of these parameters appears to be an important correlate of the response to antiviral therapy. In that setting, the pathogenic mechanisms involved in HCV-induced steatosis are mediated in large part by the HCV core protein, whose expression is associated with lipid droplet accumulation, changes in lipogenic gene expression and/or the activity of lipogenic proteins, and effects on mitochondrial oxidative function. The importance of genes such as peroxisome proliferator-activated receptor-alpha and the proteasome activator PA28-gamma in HCV-mediated steatosis has been elucidated from studies in genetically altered mice, and the manipulation of these and other pathways may provide an avenue for therapeutic intervention.

Chronic hepatitis C virus (HCV) infections are a significant cause of morbidity and mortality worldwide. Interferon-alpha2b treatment, alone or in combination with ribavirin, eliminates HCV from some patients, but patients infected with HCV genotype 1 viruses are cured less frequently than patients infected with HCV genotype 2 or 3 viruses. We report that HCV mRNA was detected and destroyed by the interferon-regulated antiviral 2'-5' oligoadenylate synthetase/ ribonuclease L pathway present in cytoplasmic extracts of HeLa cells. Ribonuclease L cleaved HCV mRNA into fragments 200 to 500 bases in length. Ribonuclease L cleaved HCV mRNA predominately at UA and UU dinucleotides within loops of predicted stem-loop structures. HCV mRNAs from relatively interferon-resistant genotypes (HCV genotypes 1a and 1b) have fewer UA and UU dinucleotides than HCV mRNAs from more interferon-sensitive genotypes (HCV genotypes 2a, 2b, 3a, and 3b). HCV 2a mRNA, with 73 more UA and UU dinucleotides than HCV 1a mRNA, was cleaved by RNase L more readily than HCV 1a mRNA. In patients, HCV 1b mRNAs accumulated silent mutations preferentially at UA and UU dinucleotides during interferon therapy. These results suggest that the sensitivity of HCV infections to interferon therapy may correlate with the efficiency by which RNase L cleaves HCV mRNA.

HCV (hepatitis C virus) infects nearly 3% of the population worldwide and has emerged as a major causative agent of liver disease, resulting in acute and chronic infections that can lead to fibrosis, cirrhosis and hepatocellular carcinoma. Hepatitis C represents the leading cause of liver transplantation in the United States and Europe. A positive-strand RNA virus of the Flaviviridae family, HCV contains a single-stranded RNA genome of approx. 9600 nucleotides. The genome RNA serves as both mRNA for translation of viral proteins and the template for RNA replication. Cis-acting RNA elements within the genome regulate RNA replication by forming secondary structures that interact with each other and trans-acting factors. Although structural proteins are clearly dispensable for RNA replication, recent evidence points to an important role of several non-structural proteins in particle assembly and release, turning their designation on its head. HCV enters host cells through receptor-mediated endocytosis, and the process requires the co-ordination of multiple cellular receptors and co-receptors. RNA replication takes place at specialized intracellular membrane structures called 'membranous webs' or 'membrane-associated foci', whereas viral assembly probably occurs on lipid droplets and endoplasmic reticulum. Liver inflammation plays a central role in the liver damage seen in hepatitis C, but many HCV proteins also directly contribute to HCV pathogenesis. In the present review, the molecular and cellular aspects of the HCV life cycle and the role of viral proteins in pathological liver conditions caused by HCV infection are described.

Hepatitis C virus (HCV) induces persistent infection and causes chronic liver disease in most infected patients. Vigorous HCV-specific CD4+ and CD8+ T cell responses against HCV multiple epitopes are necessary for spontaneous viral clearance during the acute phase, but the virus appears to have multiple strategies to evade these defenses. There are relatively few studies on the role of immune responses during the chronic phase of infection. CD4+ T cell responses appear to protect against liver injury and may be important to clearance during interferon and ribavirin based therapy. Classic cytotoxic T cells (CTL) may primarily damage the liver in chronic HCV, but there may be subpopulations of T cells that protect against liver inflammation. Resolution of these outstanding questions is important to the development of a prophylactic vaccine as well as improving therapeutic options for those with chronic infection.

In addition to the link with development of hepatocellular carcinoma (HCC), hepatitis C virus (HCV) infection is associated with several hepatic and extrahepatic manifestations. A role of hepatic steatosis in the pathogenesis of chronic hepatitis C has been shown, implying hepatitis C as a metabolic disease. Furthermore, recent epidemiological studies have suggested a linkage between insulin resistance and chronic HCV infection. In addition to the data indicating the presence of lipid metabolism disturbance and insulin resistance in the cohort of chronic hepatitis C patients, we found evidence showing the association between these two conditions and HCV infection using mice transgenic for the HCV core gene. These mice develop HCC late in life after the phase of hepatic steatosis and insulin resistance. The nonappearance of both steatosis and HCC in HCV core gene transgenic mice that are null for the proteasome activator 28gamma implies a close relationship between lipid metabolism disturbance and hepatocarcinogenesis. Also, the core protein is shown to bind with retinoid X receptor (RXR)-alpha, resulting in the upregulation of some lipid metabolism enzymes, including cellular retinol binding protein II and acyl-CoA oxidase. In addition, the persistent activation of peroxisome proliferator activated receptor (PPAR)-alpha has recently been found in the liver of HCV core gene transgenic mice, yielding dramatic changes in lipid metabolism and hepatocyte proliferation, including HCC development. These results would provide a clue for further understanding of the role of lipid metabolism in pathogenesis of HCV infection, including liver injury and hepatocarcinogenesis.

With a global burden of 170 million chronically infected patients and a major cause of liver cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is a major public health challenge. Recent discoveries of viral and cellular factors mediating virus-host interactions have allowed scientists to uncover the key molecular mechanisms of viral infection and escape from innate and adaptive immune responses. These include the discovery of tight junction proteins as entry factors and microRNA-122, cyclophilins and lipoproteins as host factors for virus translation, replication and production. Furthermore, global genetic analyses have identified IL-28B as a genetic factor associated with the outcome of HCV infection. These discoveries markedly advance the understanding of the molecular pathogenesis of HCV infection and uncover novel targets for urgently needed antiviral strategies.

Hepatitis C virus (HCV) is a major cause of chronic liver disease, with about 170 million people infected worldwide. Up to 70% of patients will have persistent infection after inoculation, making this disease a significant cause of morbidity and mortality. The severity of disease varies widely, from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma. Since the discovery of HCV, the treatment of hepatitis C has considerably improved. Recently, combination of pegylated interferons with ribavirin gives a response rate of about 55%. Treatment is indicated in patients with moderate or severe fibrosis. The tolerability of combination treatment is relatively poor, with a frequent flu-like syndrome and an impaired quality of life. In addition to viral and environmental behavioural factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes in HCV infection. The sequencing of the human genome, together with the development of high-throughput technologies that measure the function of the genome, have afforded unique opportunities to develop profiles that can distinguish, identify and classify discrete subsets of disease, predict the disease outcome or predict the response to treatment. This paper reviews the published literature on gene expression associated with HCV infection (HCV infection, fibrosis progression), and also according to response to treatment.

Since its discovery in 1989, Hepatitis C Virus (HCV) has been recognized as a major cause of chronic hepatitis, end-stage cirrhosis and hepatocellular carcinoma affecting world wide more than 210 million people. The fact that 80% of newly infected patients fail to control infection, the slow development of overt disease and immune-response as well as the unsatisfying results of current IFN/ribavirin combination therapy suggests that the hepatitis C virus developed powerful strategies to evade and to antagonize the immune response of the host and to resist the antiviral actions of interferons. During the last 10 years several viral strategies have been uncovered for control and evasion from cellular antiviral host response initiated by the pathogen-associated molecular pattern recognizing receptors RIG1 and TLR3 and mediated by the release of type I interferon and subsequent induction of interferon stimulated genes. This review highlights recent results providing an idea of how the hepatitis C virus interferes with the different steps of initial antiviral host-response and establishes persistent infection.

In summary, HCV-cell interactions include those directly involved with the HCV life cycle such as virus attachment, entry, and replication. Included within this broad area of research are the interactions of HCV proteins with the IFN system, cytokine and chemokine pathways such as IL-8, and various other cellular proteins and pathways. The plethora of contradictory and sometimes confusing accessory HCV-host interactions defies precise predictions of their role in HCV biology. It is clear that these virus-cell interactions affect HCV replication, antiviral resistance, persistence, and pathogenesis. Because HCV-host interactions are initiated immediately on infection, they are operative during acute HCV infection, whereby HCV interacts with innate cellular antiviral and immune systems. The magnitude and duration of these HCV-host interactions therefore may influence the development of acquired immunity. Because HCV exists as a quasispecies in all infected individuals, heterogeneity in biological responses to HCV-host interactions is predicted, revealing opportunities for the development of various genotypic and phenotypic prognostic indicators. With the model systems in place, these hypotheses can be tested. The challenge for the future is to determine if there is a hierarchical importance to these interactions, to delineate how these virus-cell interactions affect the patient infected with HCV, and to determine whether any of these interactions represents a target for therapeutic intervention.

Hepatitis C virus (HCV) is a global public health problem that mediates a persistent infection in nearly 200 million people. HCV is efficient in establishing chronicity due in part to the inefficiency of the host immune system in controlling and counteracting HCV-mediated evasion strategies. HCV persistence is linked to the ability of the virus to suppress the RIG-I pathway and interferon production from infected hepatocytes, thus evading innate immune defenses within the infected cell. This review describes the virus and host processes that regulate the RIG-I pathway during HCV infection. An understanding of these HCV-host interactions could lead to more effective therapies for HCV designed to reactivate the host immune response following HCV infection.