https://www.gastrojournal.org/article/S0016-5085(04)01593-8/pdf

Hepatocellular carcinoma in cirrhosis: incidence and risk factors.

Among the many viruses that are known to infect the human liver, hepatitis B virus (HBV) and hepatitis C virus (HCV) are unique because of their prodigious capacity to cause persistent infection, cirrhosis, and liver cancer. HBV and HCV are noncytopathic viruses and, thus, immunologically mediated events play an important role in the pathogenesis and outcome of these infections. The adaptive immune response mediates virtually all of the liver disease associated with viral hepatitis. However, it is becoming increasingly clear that antigen-nonspecific inflammatory cells exacerbate cytotoxic T lymphocyte (CTL)-induced immunopathology and that platelets enhance the accumulation of CTLs in the liver. Chronic hepatitis is characterized by an inefficient T cell response unable to completely clear HBV or HCV from the liver, which consequently sustains continuous cycles of low-level cell destruction. Over long periods of time, recurrent immune-mediated liver damage contributes to the development of cirrhos...

Immunobiology and pathogenesis of viral hepatitis.

Collectively, the results summarized in this review suggest that HBV acts like a stealth virus early in infection, remaining undetected and spreading until the onset of the adaptive immune response several weeks later. We suspect that the relative invisibility of HBV to the innate sensing machinery of the cells reflects its replication strategy, which sequesters the transcriptional template in the nucleus, entails the production of capped and polyadenylated viral mRNAs that resemble the structure of normal cellular transcripts, and the replicating viral genome is sheltered within viral capsid particles in the cytoplasm and, therefore, does not elicit a response. In contrast, HCV activates a strong intracellular antiviral response in the liver, presumably because it replicates via a dsRNA intermediate in the cytoplasm, where it can readily induce the cellular dsRNA sensing apparatus and initiate the signaling cascade. In turn, this results in the induction of many genes, such as the 2′,5′-oligoadenylate synthetase Mx1, that have known antiviral activity (reviewed in references 128 and 141); TRIM14 and 22, members of the same gene family as TRIM5, which has been shown to be part of the host defense against retroviruses (reviewed in reference 11); and ISG15, which has recently been proposed to have a role in innate immunity (124). Impressively, however, HCV cunningly manages to spread through the liver despite induction of these genes, presumably because its E2, NS3, and NS5A proteins can defeat them. On the other hand, both viruses can be controlled when CD8+ T cells enter the liver, recognize antigen, kill whatever infected cells they encounter, and secrete IFN-γ, which triggers a broad-based cascade that amplifies the inflammatory process and has antiviral activity, at least in HBV-transgenic mice and the HBV and HCV cell culture systems. The unexpected finding that HBV does not modulate host cellular gene transcription and apparently does not induce an innate immune response when spreading through the liver raises the possibility that HBV, unlike HCV and other viruses, has evolved to evade innate immunity by not inducing it rather then actively counteracting it; this, in turn, might leave HBV very sensitive to intracellular antiviral mechanisms when they are induced by the adaptive immune system or an unrelated viral infection. Although we suggest that HBV and HCV infections can be inhibited noncytopathically by the cellular genes that are induced during this process, the identities of those genes, the antiviral mechanisms they elicit, and the unique evasion strategies of each virus remain to be determined, marking a new starting point in the quest to understand the cellular and molecular immunobiology of these viral infections.

https://jvi.asm.org/content/jvi/79/15/9369.full.pdf

Stealth and cunning: hepatitis B and hepatitis C viruses.

Chronic infection with the hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. The pathogenesis of HCC in HCV infection has extensively been analysed. Hepatitis C virus-induced chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation are considered as one of the major pathogenic mechanisms. Increasing experimental evidence suggests that HCV contributes to HCC by directly modulating pathways that promote the malignant transformation of hepatocytes. Hepatitis C virus is an RNA virus that does not integrate into the host genome but HCV proteins interact with many host-cell factors well beyond their roles in the viral life cycle and are involved in a wide range of activities, including cell signaling, transcription, cell proliferation, apoptosis, membrane rearrangements, vesicular trafficking and translational regulation. At least four of the HCV gene products, namely HCV core, NS3, NS4B and NS5A, have been shown to exhibit transformation potential in tissue culture and several potentially oncogenic pathways have been shown to be altered by the expression of HCV proteins. Both HCV core and NS5A induce the accumulation of wild-type beta-catenin and the Wnt-beta-catenin pathway emerges as a common target for HCV (and HBV) in human HCCs, also independently from axin/beta-catenin gene mutations. Induction of both endoplasmic reticulum stress and oxidative stress by HCV proteins might also contribute to HCV transformation. Most of the putative transforming functions of the HCV proteins have been defined in artificial cellular systems, which may not be applicable to HCV infection in vivo, and still need to be established in relevant infection and disease models.

/pdf/viral-hepatitis-and-liver-cancer-the-case-of-hepatitis-c-pc5x8vutsa.pdf

Viral hepatitis and liver cancer: the case of hepatitis C.

Hepatitis C Virus Core Protein Inhibits Mitochondrial Electron Transport and Increases Reactive Oxygen Species (ROS) Production

https://www.gastrojournal.org/article/S0016-5085(02)73468-9/pdf

Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus.

Adult Syrian golden hamsters inoculated intraperitoneally with Pirital virus, a recently discovered member of the Tacaribe complex of New World arenaviruses, developed a progressively severe, fatal illness with many of the pathologic features observed in fatal human cases of Lassa fever and other arenaviral hemorrhagic fevers. Most of the animals became moribund by Day 5 and were dead by Day 7 after inoculation. The most consistent histopathologic changes included interstitial pneumonitis, splenic lymphoid depletion and necrosis, and multifocal hepatic necrosis without significant inflammatory cell infiltration. The liver changes ranged from single cell death by apoptosis to coagulative necrosis of clusters of hepatocytes. Immunohistochemical studies of the liver demonstrated the presence and accumulation ot Pirital virus antigen within hepatocytes as well as Kupffer cells. An in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay showed progressively increasing apoptotic activity in the liver of infected hamsters. A human hepatoblastoma cell line (Hep G2/C3A) inoculated with Pirital virus also developed progressive cell destruction and accumulation of viral antigen, as demonstrated by immunofluorescence. Results of this pilot study suggest that the Pirital virus-hamster model is a very promising new small animal model for studying the pathogenesis of arenavirus infections, particularly, the mechanism of direct virus-induced hepatic injury. It may also be useful for testingantiviral agents for treatment of arenaviral hemorrhagic fevers.

Yan Yang

Papers

Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus.

Pirital virus (Arenaviridae) infection in the syrian golden hamster, Mesocricetus auratus: a new animal model for arenaviral hemorrhagic fever.