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Open AccessEditorial

Hepatitis B and C Viruses and Hepatocellular Carcinoma

by Birke Bartosch

Viruses 2010, 2(8), 1504-1509; https://doi.org/10.3390/v2081504 - 27 Jul 2010

Cited by 39 | Viewed by 10729

Abstract

Chronic liver disease is responsible for over 1.4 million deaths annually [1] and is characterized by permanent inflammatory processes that predispose to liver cancer and in particular hepatocellular carcinoma (HCC). In healthy liver, inflammatory processes stimulate growth and repair and restore normal liver [...] Read more.

Chronic liver disease is responsible for over 1.4 million deaths annually [1] and is characterized by permanent inflammatory processes that predispose to liver cancer and in particular hepatocellular carcinoma (HCC). In healthy liver, inflammatory processes stimulate growth and repair and restore normal liver architecture. However, if liver inflammation becomes chronic, the balance of damage versus regeneration in the liver is disrupted and can lead to the formation of excessive scar tissue, termed fibrosis. In the long-term, an exacerbation of fibrosis will lead to cirrhosis, which is characterized by abnormal liver architecture and function and is associated with a significant reduction in overall health and wellbeing. At cirrhotic stages, liver damage is often irreversible or difficult to treat. Cirrhosis leads frequently to death from liver failure or to HCC (Figure 1). Indeed, HCC is the first cause of death in cirrhotic patients [2], and is a tumor with poor prognosis, ranking third in terms of death by cancer. Furthermore, it is the fifth most prevalent cancer worldwide, with 800,000 new cases per year in the world [2,3]. [...] Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Research

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Open AccessArticle

Liver Cell Transformation in Chronic HBV Infection

by Shirine Benhenda, Delphine Cougot, Christine Neuveut and Marie Annick Buendia

Viruses 2009, 1(3), 630-646; https://doi.org/10.3390/v1030630 - 30 Oct 2009

Cited by 10 | Viewed by 14187

Abstract

Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma (HCC), but the molecular mechanisms underlying virally-induced tumorigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, [...] Read more.

Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma (HCC), but the molecular mechanisms underlying virally-induced tumorigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, indirect roles have been proposed, including insertional activation of cellular oncogenes by HBV DNA integration, induction of genetic instability by viral integration or by the regulatory protein HBx, and long term effects of viral proteins in enhancing immune-mediated liver disease. In this chapter, we discuss different models of HBV-mediated liver cell transformation based on animal systems of hepadnavirus infection as well as functional studies in hepatocyte and hepatoma cell lines. These studies might help identifying the cellular effectors connecting HBV infection and liver cell transformation. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Review

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Open AccessReview

Innate Antiviral Immune Responses to Hepatitis B Virus

by Malika Ait-goughoulte, Julie Lucifora, Fabien Zoulim and David Durantel

Viruses 2010, 2(7), 1394-1410; https://doi.org/10.3390/v2071394 - 5 Jul 2010

Cited by 55 | Viewed by 19936

Abstract

Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis in humans. As HBV itself is currently viewed as a non-cytopathic virus, the liver pathology associated with hepatitis B is mainly thought to be due to immune responses directed against [...] Read more.

Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis in humans. As HBV itself is currently viewed as a non-cytopathic virus, the liver pathology associated with hepatitis B is mainly thought to be due to immune responses directed against HBV antigens. The outcome of HBV infection is the result of complex interactions between replicating HBV and the immune system. While the role of the adaptive immune response in the resolution of HBV infection is well understood, the contribution of innate immune mechanisms remains to be clearly defined. The innate immune system represents the first line of defense against viral infection, but its role has been difficult to analyze in humans due to late diagnosis of HBV infection. In this review, we discuss recent advances in the field of innate immunity to HBV infection. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

Antiviral Treatment of Chronic Hepatitis B Virus (HBV) Infections

by Erik De Clercq, Geoffrey Férir, Suzanne Kaptein and Johan Neyts

Viruses 2010, 2(6), 1279-1305; https://doi.org/10.3390/v2061279 - 31 May 2010

Cited by 56 | Viewed by 15253

Abstract

While 25 compounds have been formally licensed for the treatment of HIV infection (AIDS), only seven licensed products are currently available for the treatment of chronic hepatitis B virus (HBV) infection: interferon-α, pegylated interferon-α, lamivudine, adefovir (dipivoxil), entecavir, telbivudine and tenofovir (disoproxil fumarate). [...] Read more.

While 25 compounds have been formally licensed for the treatment of HIV infection (AIDS), only seven licensed products are currently available for the treatment of chronic hepatitis B virus (HBV) infection: interferon-α, pegylated interferon-α, lamivudine, adefovir (dipivoxil), entecavir, telbivudine and tenofovir (disoproxil fumarate). In contrast to the treatment of HIV infections where the individual drugs are routinely used in combination, for the treatment of chronic HBV infection the individual drugs are generally used in monotherapy. In principle, combination drug therapy should allow reducing the likelihood of drug-resistant development. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

Antiviral Therapy for Hepatitis C Virus: Beyond the Standard of Care

by Leen Delang, Lotte Coelmont and Johan Neyts

Viruses 2010, 2(4), 826-866; https://doi.org/10.3390/v2040826 - 29 Mar 2010

Cited by 35 | Viewed by 11179

Abstract

Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Infection with HCV is the leading cause of liver transplantation in the [...] Read more.

Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Infection with HCV is the leading cause of liver transplantation in the Western world. Currently, the standard of care (SoC) consists of pegylated interferon alpha (pegIFN-α) and ribavirin (RBV). However this therapy has a limited efficacy and is associated with serious side effects. Therefore more tolerable, highly potent inhibitors of HCV replication are urgently needed. Both Specifically Targeted Antiviral Therapy for HCV (STAT-C) and inhibitors that are believed to interfere with the host-viral interaction are discussed. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

Recent Advances in Hepatitis C Virus Cell Entry

by Birke Bartosch and Jean Dubuisson

Viruses 2010, 2(3), 692-709; https://doi.org/10.3390/v2030692 - 8 Mar 2010

Cited by 20 | Viewed by 14892

Abstract

More than 170 million patients worldwide are chronically infected with hepatitis C virus (HCV). Prevalence rates range from 0.5% in Northern European countries to 28% in some areas of Egypt. HCV is hepatotropic, and in many countries chronic hepatitis C is a leading [...] Read more.

More than 170 million patients worldwide are chronically infected with hepatitis C virus (HCV). Prevalence rates range from 0.5% in Northern European countries to 28% in some areas of Egypt. HCV is hepatotropic, and in many countries chronic hepatitis C is a leading cause of liver disease including fibrosis, cirrhosis and hepatocellular carcinoma. HCV persists in 50–85% of infected patients, and once chronic infection is established, spontaneous clearance is rare. HCV is a member of the Flaviviridae family, in which it forms its own genus. Many lines of evidence suggest that the HCV life cycle displays many differences to that of other Flaviviridae family members. Some of these differences may be due to the close interaction of HCV with its host’s lipid and particular triglyceride metabolism in the liver, which may explain why the virus can be found in association with lipoproteins in serum of infected patients. This review focuses on the molecular events underlying the HCV cell entry process and the respective roles of cellular co-factors that have been implied in these events. These include, among others, the lipoprotein receptors low density lipoprotein receptor and scavenger receptor BI, the tight junction factors occludin and claudin-1 as well as the tetraspanin CD81. We discuss the roles of these cellular factors in HCV cell entry and how association of HCV with lipoproteins may modulate the cell entry process. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

HCV Innate Immune Responses

by Markus H. Heim

Viruses 2009, 1(3), 1073-1088; https://doi.org/10.3390/v1031073 - 30 Nov 2009

Cited by 5 | Viewed by 12882

Abstract

Hepatitis C virus (HCV) establishes a persistent infection in more than 70% of infected individuals. This striking ability to evade the powerful innate immune system results from viral interference occurring at several levels of the interferon (IFN) system. There is strong evidence from [...] Read more.

Hepatitis C virus (HCV) establishes a persistent infection in more than 70% of infected individuals. This striking ability to evade the powerful innate immune system results from viral interference occurring at several levels of the interferon (IFN) system. There is strong evidence from cell culture experiments that HCV can inhibit the induction of IFNβ by cleaving important proteins in the virus sensory pathways of cells such as MAVS and TRIF. There is also evidence that HCV interferes with IFNα signaling through the Jak-STAT pathway, and that HCV proteins target IFN effector systems such as protein kinase R (PKR). These in vitro findings will have to be confirmed in clinical trials investigating the molecular mechanisms of HCV interference with the innate immune system in liver samples. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

Molecular Mechanisms Underlying Hepatocellular Carcinoma

by Philippe Merle and Christian Trepo

Viruses 2009, 1(3), 852-872; https://doi.org/10.3390/v1030852 - 9 Nov 2009

Cited by 34 | Viewed by 13492

Abstract

Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem [...] Read more.

Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem cell-like properties. The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21^Cip1and p16^INK4a/pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage. Still obscure mechanisms, but maybe involving the Wnt signaling and Twist proteins, would allow pre-senescent hepatocytes to bypass senescence, acquire immortality by telomerase reactivation and get the last genetic/epigenetic hits necessary for cancerous transformation. Among some of the oncogenic pathways that might play key driving roles in hepatocarcinogenesis, c-myc and the Wnt/β-catenin signaling seem of particular interest. Finally, antiproliferative and apoptosis deficiencies involving TGF-β, Akt/PTEN, IGF2 pathways for instance are prerequisite for cancerous transformation. Of evidence, not only the transformed liver cell per se but the facilitating microenvironment is of fundamental importance for tumor bulk growth and metastasis. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

HBV and HCV Therapy

by Pietro Lampertico, Alessio Aghemo, Mauro Viganò and Massimo Colombo

Viruses 2009, 1(3), 484-509; https://doi.org/10.3390/v1030484 - 22 Oct 2009

Cited by 8 | Viewed by 13844

Abstract

One year of interferon therapy inhibits HBV replication in one third of the patients whereas long-term administration of oral nucleos(t)ide analogues is efficient in most of them, as long as early treatment adaptation in patients with partial virological response and resistance is provided. [...] Read more.

One year of interferon therapy inhibits HBV replication in one third of the patients whereas long-term administration of oral nucleos(t)ide analogues is efficient in most of them, as long as early treatment adaptation in patients with partial virological response and resistance is provided. Following the demonstration of a more potent antiviral effect in terms of sustained virological response (SVR) rates, Pegylated-IFN coupled with Ribavirin has become the standard treatment for chronic hepatitis C, with nearly 65% of all treated patients achieving a SVR. Long-term suppression of HBV and eradication of HCV would halt the progression of chronic hepatitis to cirrhosis, hepatocellular carcinoma and liver decompensation. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

Adaptive Immunity to Hepatitis C Virus

by Mirjam B. Zeisel, Samira Fafi-Kremer, Eric Robinet, François Habersetzer, Thomas F. Baumert and Françoise Stoll-Keller

Viruses 2009, 1(2), 276-297; https://doi.org/10.3390/v1020276 - 8 Sep 2009

Cited by 4 | Viewed by 13637

Abstract

The precise role of adaptive immune responses in the clinical outcome of HCV infection is still only partially defined. Recent studies suggest that viral-host cell interactions during the acute phase of infection are essential for viral clearance or progression into chronic HCV infection. [...] Read more.

The precise role of adaptive immune responses in the clinical outcome of HCV infection is still only partially defined. Recent studies suggest that viral-host cell interactions during the acute phase of infection are essential for viral clearance or progression into chronic HCV infection. This review focuses on different aspects of the adaptive immune responses as determinants of the different outcomes of HCV infection, clearance or persistent infection, and outlines current concepts of HCV evasion strategies. Unravelling these important mechanisms of virus-host interaction will contribute to the development of novel strategies to prevent and control HCV infection. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

HCV Animal Models: A Journey of More than 30 Years

by Philip Meuleman and Geert Leroux-Roels

Viruses 2009, 1(2), 222-240; https://doi.org/10.3390/v1020222 - 2 Sep 2009

Cited by 12 | Viewed by 10126

Abstract

In the 1970s and 1980s it became increasingly clear that blood transfusions could induce a form of chronic hepatitis that could not be ascribed to any of the viruses known to cause liver inflammation. In 1989, the hepatitis C virus (HCV) was discovered [...] Read more.

In the 1970s and 1980s it became increasingly clear that blood transfusions could induce a form of chronic hepatitis that could not be ascribed to any of the viruses known to cause liver inflammation. In 1989, the hepatitis C virus (HCV) was discovered and found to be the major causative agent of these infections. Because of its narrow ropism, the in vivo study of this virus was, especially in the early days, limited to the chimpanzee. In the past decade, several alternative animal models have been created. In this review we review these novel animal models and their contribution to our current understanding of the biology of HCV. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

HBV Life Cycle: Entry and Morphogenesis

by Stephanie Schädler and Eberhard Hildt

Viruses 2009, 1(2), 185-209; https://doi.org/10.3390/v1020185 - 1 Sep 2009

Cited by 95 | Viewed by 21763

Abstract

Hepatitis B virus (HBV) is a major cause of liver disease. HBV primarily infects hepatocytes by a still poorly understood mechanism. After an endocytotic process, the nucleocapsids are released into the cytoplasm and the relaxed circular rcDNA genome is transported towards the nucleus [...] Read more.

Hepatitis B virus (HBV) is a major cause of liver disease. HBV primarily infects hepatocytes by a still poorly understood mechanism. After an endocytotic process, the nucleocapsids are released into the cytoplasm and the relaxed circular rcDNA genome is transported towards the nucleus where it is converted into covalently closed circular cccDNA. Replication of the viral genome occurs via an RNA pregenome (pgRNA) that binds to HBV polymerase (P). P initiates pgRNA encapsidation and reverse transcription inside the capsid. Matured, rcDNA containing nucleocapsids can re-deliver the RC-DNA to the nucleus, or be secreted via interaction with the envelope proteins as progeny virions. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

Prophylactic and Therapeutic Vaccination against Hepatitis C Virus (HCV): Developments and Future Perspectives

by Marian E. Major

Viruses 2009, 1(2), 144-165; https://doi.org/10.3390/v1020144 - 12 Aug 2009

Cited by 9 | Viewed by 10720

Abstract

Studies in patients and chimpanzees that spontaneously clear Hepatitis C Virus (HCV) have demonstrated that natural immunity to the virus is induced during primary infections and that this immunity can be cross protective. These discoveries led to optimism regarding prophylactic HCV vaccines and [...] Read more.

Studies in patients and chimpanzees that spontaneously clear Hepatitis C Virus (HCV) have demonstrated that natural immunity to the virus is induced during primary infections and that this immunity can be cross protective. These discoveries led to optimism regarding prophylactic HCV vaccines and a number of studies in the chimpanzee model have been performed, all of which resulted in modified infections after challenge but did not always prevent persistence of the virus. Therapeutic vaccine strategies have also been pursued in an effort to reduce the costs and side effects associated with anti-viral drug treatment. This review summarizes the studies performed thus far in both patients and chimpanzees for prophylactic and therapeutic vaccination, assesses the progress made and future perspectives. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

Hepatitis C Virus Infection: Molecular Pathways to Steatosis, Insulin Resistance and Oxidative Stress

by Sophie Clément, Stéphanie Pascarella and Francesco Negro

Viruses 2009, 1(2), 126-143; https://doi.org/10.3390/v1020126 - 11 Aug 2009

Cited by 45 | Viewed by 22231

Abstract

The persistent infection with hepatitis C virus is a major cause of chronic liver disease worldwide. However, the morbidity associated with hepatitis C virus widely varies and depends on several host-related cofactors, such as age, gender, alcohol consumption, body weight, and co-infections. The [...] Read more.

The persistent infection with hepatitis C virus is a major cause of chronic liver disease worldwide. However, the morbidity associated with hepatitis C virus widely varies and depends on several host-related cofactors, such as age, gender, alcohol consumption, body weight, and co-infections. The objective of this review is to discuss three of these cofactors: steatosis, insulin resistance and oxidative stress. Although all may occur independently of HCV, a direct role of HCV infection in their pathogenesis has been reported. This review summarizes the current understanding and potential molecular pathways by which HCV contributes to their development. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Role of Host Genetic Factors in the Outcome of Hepatitis C Virus Infection

by Bertram Bengsch, Robert Thimme and Hubert E. Blum

Viruses 2009, 1(2), 104-125; https://doi.org/10.3390/v1020104 - 5 Aug 2009

Cited by 27 | Viewed by 11511

Abstract

The natural history of hepatitis C virus (HCV) infection is determined by a complex interplay between host genetic, immunological and viral factors. This review highlights genes involved in innate and adaptive immune responses associated with different outcomes of HCV infection. For example, an [...] Read more.

The natural history of hepatitis C virus (HCV) infection is determined by a complex interplay between host genetic, immunological and viral factors. This review highlights genes involved in innate and adaptive immune responses associated with different outcomes of HCV infection. For example, an association of HCV clearance with certain HLA alleles has been demonstrated. The mechanisms responsible for these associations have been linked to specific T cell responses for some particular alleles (e.g., HLA-B27). Genetic associations involved in T cell regulation and function further underline the role of the adaptive immune response in the natural history of HCV infection. In addition, some genes involved in innate NK cell responses demonstrate the complex interplay between components of the immune system necessary for a successful host response to HCV infection. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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Open AccessReview

HBV-Specific Adaptive Immunity

by Antonio Bertoletti, Anthony T. Tan and Adam J. Gehring

Viruses 2009, 1(2), 91-103; https://doi.org/10.3390/v1020091 - 27 Jul 2009

Cited by 28 | Viewed by 12575

Abstract

The successful control of HBV infection requires an efficient expansion of distinct elements of the adaptive immune system (B cells, helper and cytotoxic T cells) that, due to the hepatotropic nature of HBV, need to operate in the liver parenchyma. In this respect, [...] Read more.

The successful control of HBV infection requires an efficient expansion of distinct elements of the adaptive immune system (B cells, helper and cytotoxic T cells) that, due to the hepatotropic nature of HBV, need to operate in the liver parenchyma. In this respect, we will discuss broad features of HBV immunity in patients with resolved or chronic HBV infection and analyze how the liver environment can directly modulate HBV-immunity. Full article

(This article belongs to the Special Issue Hepatitis Viruses)

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