A virological perspective on the need for vaccination

Superinfecton of chronic carriers of hepatitis B virus (HBV) or hepatitis C virus (HCV) with hepatitis A virus (HAV) is often associated with more severe liver disease than infection with HAV alone. Superinfection commonly causes markers of HBV and HCV replication to fall to significantly lower levels. The pathogenesis of acute liver damage characteristic of viral hepatitis is thought to be mediated by host cytotoxic T-lymphocytes (CTLs) directed against virus-infected hepatocytes. It has been proposed that the more aggressive liver disease observed in individuals infected with HAV in addition to chronic HBV/HCV is a result of the induction of interferon (IFN)-alpha during acute HAV infection. This accounts for the antiviral effect on the active markers of HBV/HCV replication, and the enhanced CTL response against HBV/HCV-infected hepatocytes. Alternatively, HAV may indirectly stimulate the T helper 1 (Th1)-type cytokine responses, such as interleukin (IL)-2, IFN-gamma and tumour necrosis factor (TNF)-alpha, which directly promote the antiviral CTL response. Clearance of HBV infection, and possible HAV and HCV, is associated with a specific CTL response, while viral persistence in chronic HBV and HCV infection has been attributed to an imbalance in the Th1-Th2 arms of the immune response. Vaccination against hepatitis A should be considered for patients with chronic HBV/HCV infection, to minimize the risk of exacerbating underlying liver disease.     

Pathogenesis of hepatocellular damage in chronic hepatitis C virus infection

Multiple factors may influence the host-virus interaction in patients infected with hepatitis C virus (HCV), and these may result in diverse disease presentations. In immune competent hosts, there is little evidence that direct cytopathicity plays a significant role in liver cell injury. However, when host conditions are altered to allow for unusually high levels of viral replication and viral protein expression (i.e., immunosuppression), HCV may induce direct hepatocellular damage. In most patients infected with HCV, a wide array of humoral and cell-mediated immune responses are triggered in response to HCV polypeptides; however, despite this host immune response, HCV infections usually persist. Furthermore, the host immune response, in its attempt to clear the virus from the liver, contributes to the hepatocellular damage (chronic hepatitis) seen in the majority of chronically infected patients.     

Hepatitis C virus infection. How does the host respond?

The interaction between the host and the hepatitis C virus (HCV) results either in elimination of the virus or establishment of chronic infection. The principal mechanisms defining the outcome of infection are complex and largely yet to be determined. The perceived lack of a robust immune response against viral replication in chronic infection may actually reflect a dangerous homeostasis reached as the virus and immune system co-exist over time. Perturbing this contemporaneous relationship by aiming to control HCV replication, or eradicate the virus, may instead bring about an undesired self-destructive immune response. Recent studies have provided us with a better understanding of the virus-host interactions and may help us unravel the immunologic components necessary for successful HCV clearance.     

Regulatory T cells in viral hepatitis

The pathogenesis and outcome of viral infections are significantly influenced by the host immune response. The immune system is able to eliminate many viruses in the acute phase of infection. However, some viruses, like hepatitis C virus (HCV) and hepatitis B virus (HBV), can evade the host immune responses and establish a persistent infection. HCV and HBV persistence is caused by various mechanisms, like subversion of innate immune responses by viral factors, the emergence of T cell escape mutations, or T cell dysfunction and suppression. Recently, it has become evident that regulatory T cells may contribute to the pathogenesis and outcome of viral infections by suppressing antiviral immune responses. Indeed, the control of HCV and HBV specific immune responses mediated by regulatory T cells may be one mechanism that favors viral persistence, but it may also prevent the host from overwhelming T cell activity and liver damage. This review will focus on the role of regulatory T cells in viral hepatitis.     

Pathogenesis of recurrent hepatitis C after liver transplantation

End-stage liver disease associated with hepatitis C virus (HCV) infection is the most common indication for liver transplantation in the United States. Recurrent HCV infection is nearly universal and disease progression is accelerated in the immunocompromised host. In the post-transplant setting, the HCV-specific immune response plays a critical role in viral surveillance and disease progression. A failure to mount an efficient response to HCV antigens, either because of selective defects in the host immune system or because of viral interference with the normal function of the immune cells, could account for the inability of most transplant recipients to eradicate HCV.     

Alcohol abuse and chronic hepatitis C

AbstractChronic infection with hepatitis C virus (HCV) and alcohol abuse are two of the most common causes of chronic liver disease in the United States. These two entities often coexist and contribute to accelerated development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although the effect of one drink per day in the setting of chronic HCV infection is unclear, there is overwhelming evidence for the deleterious effects of heavy alcohol use on HCV liver disease. The mechanisms by which alcohol increases liver injury in hepatitis C are poorly understood. Potential pathways include impaired host immune systems and increased viral replication. Alcohol use may decrease the success of treatment. Physicians should encourage patients with chronic hepatitis C to abstain from regular alcohol use.     

The immunopathogenesis of hepatitis C virus infection.

The outcome of HCV infection is determined by the interaction between the virus and the host immune system. The persistence of infection in most HCV-infected individuals, despite the presence of HCV-directed antibodies, suggests that such antibodies fail to induce viral clearance. Patients with self-limited hepatitis C have evidence of a polyclonal, multispecific CD8+ T-cell response along with a coordinated CD4+ T-cell response that is associated with eradication of HCV infection. Cytokines are produced both locally within the liver and systemically and may play an important role in controlling viral replication and contributing to hepatocellular damage through amplification of a nonspecific immune response. In most patients, the humoral, cellular immune, and cytokine response seem insufficient to eradicate infection. In its attempt to clear the virus from the liver, the immune system contributes to the hepatocellular injury seem in most chronically infected patients. A better understanding of the host's immune response may provide further insight on the pathogenetic mechanisms involved in development of chronic hepatitis and aid the development of better therapeutic strategies.     

Hepatitis C virus and antiviral innate immunity:Who wins at tug-of-war?

Hepatitis C virus(HCV) is a major human pathogen of chronic hepatitis and related liver diseases. Innate immunity is the first line of defense against invading foreign pathogens, and its activation is dependent on the recognition of these pathogens by several key sensors. The interferon(IFN) system plays an essential role in the restriction of HCV infection via the induction of hundreds of IFN-stimulated genes(ISGs) that inhibit viral replication and spread. However, numerous factors that trigger immune dysregulation, including viral factors and host genetic factors, can help HCV to escape host immune response, facilitating viral persistence. In this review, we aim to summarize recent advances in understanding the innate immune response to HCV infection and the mechanisms of ISGs to suppress viral survival, as well as the immune evasion strategies for chronic HCV infection.     

丙型肝炎病毒感染与治疗药物

丙型肝炎病毒（HCV）通过在宿主细胞内持续复制,导致慢性感染。目前用于治疗慢性丙型肝炎（CHC）的药物主要是聚乙二醇干扰素（PEG-IFN）和利巴韦林的联合用药。本文将就HCV的细胞入侵、复制、逃避宿主的固有和获得性免疫,以及抗HCV临床试验药物的最新进展做一综述。     

Effects of immunosuppression and organ transplantation on the natural history and immunopathogenesis of hepatitis C virus infection

The hepatitis C virus (HCV) is recognized as the leading cause for parenterally transmitted hepatitis. It is characterized by a high propensity to chronicity. Several efforts have been directed towards understanding the natural history of chronic HCV infection and the immunopathogenic pathways involved in mediating liver injury in the non‐immunosuppressed and immunosuppressed states. In the non‐immunosuppressed setting, liver damage seems to be largely immune mediated. In contrast, in the non‐immunosuppressed state, there are several other factors that may modify the natural course of the infection and play a role in mediating liver injury. In this review we will address the natural history, virological and immunological aspects of HCV infection. Also, the role played by immunosuppression and organ transplantation in modifying the course of the infection and the pathogenesis of liver injury will be discussed.( ^Note Editor’s introduction The role of the immune response in the pathogenesis of liver injury during hepatitis C viral infection remains to be clarified. In the immunologically normal host, liver injury is largely mediated by the host’s immune response. By contrast, McCaughan and Zekry review the available data, which suggest that, in the immunocompromised host, viral cytopathogenicity dominates the progression of liver disease. This observation demonstrates the acute need for improved antiviral therapies. The balance between immune suppression and the management of HCV infection in transplantation is precarious. Given the impact of acute rejection on disease progression and the possible links between HCV, stimulation of B‐cell proliferation and PTLD, new strategies for the management of this infection remain critical. Jay A. Fishman, MD Editor, Basic Science
)     

Immune and non-immune responses to hepatitis C virus infection

The host innate and adaptive immune systems are involved in nearly every step of hepatitis C virus(HCV) infection. In patients,the outcome is determined by a series of complex host-virus interactions,whether it is a natural infection or results from clinical intervention. Strong and persistent CD8+ and CD4+ T-cell responses are critical in HCV clearance,as well as cytokineinduced factors that can directly inhibit virus replication. Newly available direct-acting antivirals(DAAs) are very effective in viral clearance in patients. DAA treatment may further result in the down-regulation of programmed death-1,leading to rapid restoration of HCV-specific CD8+ T cell functions. In this review,we focus on recent studies that address the host responses critical for viral clearance and disease resolution. Additional discussion is devoted to the prophylactic vaccine development as well as to current efforts aimed at understanding the host innate responses against HCV infection. Current theories on how the ubiquitin system and interferon-stimulated genes may affect HCV replication are also discussed.     

6 Immunopathogenesis of viral hepatitis

More than 500 million people world-wide suffer from viral hepatitis which can be caused by a variety of distinct infectious agents. The spectrum of disease, which ranges from acute self-limited hepatitis to liver cirrhosis, not only reflects the different biological properties and pathogenicity of the hepatitis viruses, but is also the result of the specific interaction between each virus and the immune system of the infected host. The immune response plays a crucial role in the elimination of the infecting virus as well as in disease pathogenesis and is described in detail for acute and chronic hepatitis B and C virus infection. Acute hepatitis B virus infection is characterized by a vigorous, polyclonal cytotoxic T lymphocyte response against HBV that is not readily detectable in patients with chronic hepatitis B, suggesting that resolution of disease is mediated by the HBV-specific CTL response in these patients. Because traces of virus as well as HBVspecific CTL can perist for decades after clinical recovery, continuous priming of new CTL by minute traces of virus is thought to protect from reactivation of disease. In contrast, the hepatitis C virus causes chronic liver disease despite a polyclonal and multispecific immune response, suggesting that distinct immunological and viral mechanisms determine the different clinical outcome of HBV and HCV infection. Their implications for the development of immunomodulatory vaccines to cure patients with chronic viral hepatitis are discussed.     

Role of viral and host factors in HCV persistence: which lesson for therapeutic and preventive strategies?

Several lines of evidence support the view that hepatitis C virus is not directly cytopathic for infected host cells and that the immune response plays a central role in the pathogenesis of liver damage. Innate and adaptive immune responses are induced in most individuals infected with hepatitis C virus but are insufficient to eliminate the virus. The mechanisms responsible for this failure are largely unknown but the kinetics of hepatitis C virus replication relative to the priming of the adaptive responses may exert a profound influence on the balance between virus and host. Immediately after hepatitis C virus infection, the virus replicates efficiently, inducing the production of type I interferons. However, the rapid increase in viral replication seems to be ignored by the adaptive immune response, and after a short interval from exposure, viral load can reach levels comparable to those of patients with established persistent infection. The CD8-mediated response shows functional defects, with impaired production of interferon-gamma, low perforin content, decreased capacity of expansion and lysis of target cells. Late appearance and functional defects of T cells in hepatitis C virus infection might be the result of the rapid increase of the viral load that could create the conditions for exhaustion of the adaptive response or reflect an insufficient function of the innate immune response. This possibility is suggested by in vitro studies showing that hepatitis C virus gene products can interfere with the anti-viral activity of type I interferons and natural killer cells as well as with the maturation of dendritic cells. While T-cell defects are reversed in a minority of infected individuals who succeed in controlling the infection, the T-cell impairment becomes progressively more profound as infection progresses to chronicity. In this situation, therapeutic restoration of adaptive responses may represent a rational strategy to obtain resolution of infection and to complement available therapies. The peculiar kinetics of hepatitis C virus replication and T-cell induction soon after infection may have important implications also for the design of protective vaccines since memory responses may not be able to precede the early peak of viral replication. Therefore, vaccines against hepatitis C virus may be unable to prevent infection but may rather be effective in facilitating a self-limited evolution of infection.     

Hepatitis B virus infection and alcohol consumption

Hepatocellular carcinoma(HCC) is the most common type of primary liver cancer, and the second most common cause of cancer deaths worldwide. The top three causes of HCC are hepatitis B virus(HBV),hepatitis C virus(HCV), and alcoholic liver disease. Owing to recent advances in direct-acting antiviral agents, HCV can now be eradicated in almost all patients. HBV infection and alcoholic liver disease are expected, therefore, to become the leading causes of HCC in the future. However, the association between alcohol consumption and chronic hepatitis B in the progression of liver disease is less well understood than with chronic hepatitis C. The mechanisms underlying the complex interaction between HBV and alcohol are not fully understood, and enhanced viral replication, increased oxidative stress and a weakened immune response could each play an important role in the development of HCC. It remains controversial whether HBV and alcohol synergistically increase the incidence of HCC. Herein, we review the currently available literature regarding the interaction of HBV infection and alcohol consumption on disease progression.     

Activation of unfolded protein response and autophagy during HCV infection modulates innate immune response

Autophagy, a process for catabolizing cytoplasmic components, has been implicated in the modulation of interactions between RNA viruses and their host. However, the mechanism underlying the functional role of autophagy in the viral life cycle still remains unclear. Hepatitis C virus (HCV) is a single-stranded, positive-sense, membrane-enveloped RNA virus that can cause chronic liver disease. Here we report that HCV induces the unfolded protein response (UPR), which in turn activates the autophagic pathway to promote HCV RNA replication in human hepatoma cells. Further analysis revealed that the entire autophagic process through to complete autolysosome maturation was required to promote HCV RNA replication and that it did so by suppressing innate antiviral immunity. Gene silencing or activation of the UPR-autophagy pathway activated or repressed, respectively, IFN-β activation mediated by an HCV-derived pathogen-associated molecular pattern (PAMP). Similar results were achieved with a PAMP derived from Dengue virus (DEV), indicating that HCV and DEV may both exploit the UPR-autophagy pathway to escape the innate immune response. Taken together, these results not only define the physiological significance of HCV-induced autophagy, but also shed light on the knowledge of host cellular responses upon HCV infection as well as on exploration of therapeutic targets for controlling HCV infection.     

Association of the HLA-DRB1*01 allele with spontaneous viral clearance in an Irish cohort infected with hepatitis C virus via contaminated anti-D immunoglobulin

BACKGROUND/AIMS: The host's immune response may influence the course of hepatitis C virus (HCV) infection. The aim of this study was to examine the distribution of HLA Class II DRB1* alleles in a homogeneous cohort of individuals who were infected with HCV-contaminated anti-D immunoglobulin, and to compare frequencies of alleles in individuals with spontaneous viral clearance to those with chronic HCV infection. METHODS: HLA DRB1* typing was performed on whole blood or serum from 157 females. Of these, 73 had spontaneously recovered from infection (persistently HCV RNA negative), while 84 had chronic HCV infection (persistently HCV RNA positive). A group of 5000 healthy bone marrow donors served as a control population. RESULTS: No significant differences were observed between individuals with spontaneous viral clearance or chronic HCV infection for age, sex, alcohol consumption, source or duration of infection. The DRB1*01 allele was found significantly more frequently in individuals with viral clearance compared to those with chronic infection (27.4% vs. 7.1% p = 0.001, odds ratio OR = 4.9, pc = 0.01). No significant association was shown between severity of liver disease and DRB1* alleles. CONCLUSIONS: DRB1*01 is associated with spontaneous viral clearance in an Irish cohort infected with HCV via contaminated anti-D immunoglobulin. HLA-DRB1* genes do not appear to influence severity of liver disease. These results suggest that host HLA-DRB1* alleles are important contributors to disease outcome.     

Immunometabolic Effect of Cholesterol in Hepatitis C Infection: Implications in Clinical Management and Antiviral Therapy

Hepatitis C virus (HCV) is a lipid-enveloped virion particle that causes infection to the liver, and as part of its life cycle, it disrupts the host lipid metabolic machinery, particularly the cholesterol synthesis pathway. The innate immune response generated by liver resident immune cells is responsible for successful viral eradication. Unfortunately, most patients fail to eliminate HCV and progress to chronic infection. Chronic infection is associated with hepatic fat accumulation and inflammation that triggers fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Despite that the current direct-acting antiviral agents have increased the cure rate of HCV infection, viral genotype and the host genetic background influence both the immune response and lipid metabolism. In this context, recent evidence has shown that cholesterol and its derivatives such as oxysterols might modulate and potentialize the hepatic innate immune response generated against HCV. The impairment of the HCV life cycle modulated by serum cholesterol could be relevant for the clinical management of HCV-infected patients before and after treatment. Alongside, cholesterol levels are modulated either by genetic variations in IL28B, ApoE, and LDLR or by dietary components. Indeed, some nutrients such as unsaturated fatty acids have demonstrated to be effective against HCV replication. Thus, cholesterol modifications may be considered as a new adjuvant strategy for HCV infection therapy by providing a biochemical tool that guides treatment decisions, an improved treatment response and favoring viral clearance. Herein, the mechanisms by which cholesterol contributes to the immune response against HCV infection and how genetic and environmental factors may affect this role are reviewed.     

Hepatitis C virus and neurological damage

Chronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders.     

Viral, host and interferon-related factors modulating the effect of interferon therapy for hepatitis C virus infection

The estimated prevalence of hepatitis C virus infection in the US is approximately 1.8%. Although interferon monotherapy and combination therapy of interferon with ribavirin represent mainstay for treating HCV infection, the rate of sustained virologic response remains suboptimal. The growing evidence suggested that the clinical sequence and treatment response of chronic hepatitis C are determined by a dynamic, complex tripartite relationship among HCV infection, the host immune response, and the effect of different interferon regimens. The treatment response is associated with various viral factors including the pretreatment viral level, dynamic change of viral level during treatment, viral genotype quasispecies and nucleotide mutation in nonstructural protein 5A of hepatitis C virus. Host factors that may affect treatment response include age, gender, race, HLA alleles and the host immune responses. Interferon regimens, including type, dose, frequency and duration of treatment and combination of interferon with other anti-HCV agents also alter the therapeutic response. Understanding these complicated interaction may provide better insights into the mechanism(s) of interferon response, leading to more effective clinical application of interferon therapy.