Hepatitis B and hepatitis C

Hepatitis B and C are worldwide infectious hepatitides which are distinct in terms of epidemiology and molecular biology, but which may be quite similar in terms of clinical manifestations and histopathology, in both the acute and chronic stages. Hepatitis B virus (HBV), the human prototype of the Hepadnaviridae family of viruses is not directly cytopathic and viral hepatitis is caused by the cellular immune response to HBV. Patients infected with HBV may also have hepatitis D (delta) virus (HDV) infection, either as co-infection or a superinfection. Hepatitis D virus does not infect independently. Better control of HBV has also led to a decline in the incidence of HDV. Hepatitis C virus (HCV) is on of the Flaviviridae family of viruses, and is quite heterogeneous, with six major genotypes and more than 100 subtypes. Hepatitis C virus circulates as quasispecies that result from mutations accumulated over time, which probably enable HCV to replicate efficiently or resist immune mechanisms. Quasispecies have complicated vaccine development. Both HBV and HCV will recur in the transplanted liver. The risk of developing hepatocellular carcinoma is significantly greater in both HBV- and HCV-infected individuals.     

Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms

After hepatitis B virus (HBV) infection, liver injury and viral control have been thought to result from lysis of infected hepatocytes by virus-specific cytotoxic T cells. Patients are usually studied only after developing significant liver injury, and so the viral and immune events during the incubation phase of disease have not been defined. During a single-source outbreak of HBV infection, we identified patients before the onset of symptomatic hepatitis. The dynamics of HBV replication, liver injury, and HBV-specific CD8+ and CD4+ cell responses were investigated from incubation to recovery. Although a rise in alanine transaminase (ALT) levels was present at the time of the initial fall in HBV-DNA levels, maximal reduction in virus level occurred before significant liver injury. Direct ex vivo quantification of HBV-specific CD4+ and CD8+ cells, by using human leukocyte antigen (HLA) class I tetramers and intracellular cytokine staining, showed that adaptive immune mechanisms are present during the incubation phase, at least 4 weeks before symptoms. The results suggest that the pattern of reduction in HBV replication is not directly proportional to tissue injury during acute hepatitis B in humans. Furthermore, because virus-specific immune responses and significant reductions in viral replication are seen during the incubation phase, it is likely that the immune events central to viral control occur before symptomatic disease.     

Epidemic of hepatitis B with high mortality in India: association of fulminant disease with lack of CCL4 and natural killer T cells

An explosive outbreak of Hepatitis B with high mortality was reported in 2009, in Modasa, Gujarat, India. Mortality was associated with basal core promoter and precore mutant hepatitis B virus (HBV). The current study addresses the role of immunological parameters in the progression to fulminant hepatitis. The study population comprised of 22 acute HBV patients, 13 fulminant HBV liver failure patients and 54 healthy controls. Hepatitis B surface antigen-induced CTL responses by enzyme-linked immunosorbent spot (ELISPOT), cytokine and chemokine quantitation by Bioplex assay, peripheral NK, natural killer T (NKT), CD4 and CD8 T-cell frequencies by flow cytometry were carried out. The median percentage of NK cells in the lymphocytes of the acute and fulminant liver failure patients were significantly lower compared to controls. Acute and fulminant liver failure patients had significantly high and comparable NKT cells compared to controls, respectively. Importantly, NKT cells were significantly lower in fulminant HBV liver failure than acute HBV patients. Circulating peripheral CD4/CD8 T-cell subsets among the patient categories and controls were comparable. In acute HBV patients, a significant increase in IFN-γ release was recorded (ELISPOT) by the unstimulated, antigen-stimulated and mitogen-stimulated cells when compared to controls. Comparisons of cytokines and chemokines among the disease categories revealed significantly lower levels of CCL4 in fulminant liver failure patients. NKT cells and CCL4 might be playing a pivotal role in limiting HBV infection among the patients investigated.     

Innate antiviral immune responses to hepatitis B virus

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.     

Innate immune recognition of hepatitis B virus

Hepatitis B virus(HBV) is a hepatotropic DNA virus and its infection results in acute or chronic hepatitis. It is reported that the host innate immune system contributes to viral control and liver pathology, while whether and how HBV can trigger the components of innate immunity remains controversial. In recent years, the data accumulated from HBV-infected patients, cellular and animal models have challenged the concept of a stealth virus for HBV infection. This editorial focuses on the current findings about the innate immune recognition to HBV. Such evaluation could help us to understand HBV immunopathogenesis and develop novel immune therapeutic strategies to combat HBV infection.     

Role of viral factors in the natural course and therapy of chronic hepatitis B

Hepatitis B virus (HBV) infection is a global health problem that causes a wide spectrum of liver disease, including acute or fulminant hepatitis, inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of hepatocyte damage associated with HBV is mainly through immune-mediated mechanisms. On the basis of the virus and host interactions, the natural history of HBV carriers who are infected in early life can be divided into four dynamic phases. The frequency, extent, and severity of hepatitis flares or acute exacerbation in the second immune clearance and/or fourth reactivation phase predict liver disease progression in HBV carriers. In the past decade, hepatitis B viral factors including serum HBV DNA level, genotype, and naturally occurring mutants predictive of clinical outcomes have been identified. The higher the serum HBV DNA level after the immune clearance phase, the higher the incidence of adverse outcomes over time. In addition, high viral load, genotype C, basal core promoter mutation, and pre-S deletion correlate with increased risk of cirrhosis and HCC development. As to the treatment of chronic hepatitis B, patients with high HBV DNA level and genotype C or D infection are shown to have a worse response to interferon therapy. In conclusion, serum HBV DNA level, genotype, and naturally occurring mutants are identified to influence liver disease progression and therapy of chronic hepatitis B. More investigations are needed to clarify the molecular mechanisms of the viral factors involved in the pathogenesis of each stage of liver disease and the response to antiviral treatments.     

Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells

The innate immunopathogenesis responsible for the susceptibility to hepatocyte injury in chronic hepatitis B surface antigen carriers is not well defined. In this study, hepatitis B virus (HBV) transgenic mice (named HBs-Tg) were oversensitive to liver injury after immunologic [polyinosinic:polycytidylic acid or concanavalin A (ConA)] or chemical (CCl4) triggering. It was then found that the nonhepatotoxic low dose of ConA for wild-type mice induced severe liver injury in HBs-Tg mice, which was dependent on the accumulated intraheptic natural killer (NK) cells. Expressions of NKG2D ligands (Rae-1 and Mult-1) in hepatocytes were markedly enhanced upon ConA stimulation in HBs-Tg mice, which greatly activated hepatic NK cells via NKG2D/Rae-1 or Mult-1 recognition. Interestingly, the presence of NK T cells was necessary for NK cell activation and worked as positive helper cell possibly by producing interferon-gamma and interleukin-4 in this process. CONCLUSION: Our findings for the first time suggested the critical role of NKG2D recognition of hepatocytes by NK cells in oversensitive liver injury during chronic HBV infection.     

Pathogenesis of hepatitis B virus infection

Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Infection with HBV is one of the most common viral diseases affecting man. Both viral factors as well as the host immune response have been implicated in the pathogenesis and clinical outcome of HBV infection. In this review, we will discuss the impact of virus-host interactions for the pathogenesis of HBV infection and liver disease. These interactions include the relevance of naturally occurring viral variants for clinical disease, the role of virus-induced apoptosis for HBV-induced liver cell injury and the impact of antiviral immune responses for outcome of infection.     

Influence of human immunodeficiency virus infection on cell-mediated immunity in chronic D hepatitis.

To determine whether the abnormalities of cell-mediated immunity described in chronic D hepatitis are associated with hepatitis D virus (HDV) infection or concomitant human immunodeficiency virus (HIV) infection, serologic and tissue hepatitis B virus (HBV) and HDV markers and T lymphocyte subsets were studied in serum samples from 38 patients with chronic D hepatitis, 26 of whom had HIV infection. Patients with chronic D hepatitis and HIV infection had significantly lower peripheral blood T4:T8 ratios resulting from a significant increase in T8+ (suppressor/cytotoxic) cells, while numbers of T lymphocyte subsets were normal in cases with chronic D hepatitis only. HIV+ patients showed an increase in HBV replication (identified by hepatitis B core antigen in liver and hepatitis B e antigen and HBV DNA in serum) and in HDV replication (tissue D antigen and HDV RNA) without evidence of more active liver disease. Probably the immunologic disturbances detected in chronic D hepatitis are secondary to HIV infection, do not contribute to the pathogenesis of liver injury, and are associated with increased viral B and D replication.     

Clinical features of hepatitis d

Hepatitis D is caused by infection with hepatitis D virus (HDV), a defective RNA virus that requires the obligatory helper function of hepatitis B virus (HBV) for its in vivo transmission. Thus, HDV is acquired only by coinfection with HBV or by superinfection of an HBV carrier. The clinical outcome of hepatitis D differs according to the modality of infection. Whereas coinfection evolves to chronicity in only 2% of the cases, superinfection results in chronic infection in over 90% of the cases. HDV is a highly pathogenic virus that causes acute, often fulminant hepatitis, as well as a rapidly progressive form of chronic viral hepatitis, leading to cirrhosis in 70 to 80% of the cases. The clinical picture of HDV disease is evolving as a consequence of a significant change in the epidemiology of HDV infection, which has led to a significant decline in incidence in Western countries, mainly as a result of universal HBV vaccination programs. However, in the face of a declining prevalence in areas of old endemicity like Europe, immigration poses a threat of HDV resurgence. The interaction of HDV with other hepatitis viruses or human immunodeficiency virus is complex and may lead to different patterns in terms of virologic expression and immunologic responses. Multiple viral infections are associated with rapid progression of liver fibrosis and eventually with the development of hepatocellular carcinoma. Hepatitis D is not a vanishing disease, and continuous efforts should be made to improve its prevention and treatment.     

Activation and function of hepatic NK cells in hepatitis B infection: an underinvestigated innate immune response

Natural killer (NK) cells are abundant in the normal liver, accounting for around one-third of intrahepatic lymphocytes and are important in the defence against hepatitis B virus (HBV) infection as innate immune responses. In this review, we discuss the mechanisms of hepatic NK cell activity against HBV. Whether directly activated by HBV infection or indirectly activated by other lymphocytes such as NKT cells or antigen-presenting cells (APCs), hepatic NK cells exert their anti-viral functions by natural cytotoxicity and production of high levels of cytokines. However, activated NK cells play an important role in regulating adaptive immune responses by interaction with other lymphocytes such as T, B and APCs. In addition, NK cells may contribute to the lymphocyte-mediated liver injury during HBV infection that was previously considered to be mediated only by CD8+ T cells or/and NKT cells.     

The expression and function of NKG2D molecule on intrahepatic CD8+ T cells in chronic viral hepatitis

Summary. The natural killer (NK) cell receptor, NKG2D is a member of the c‐type lectin‐activating receptor family. It is expressed by all NK cells and by a sub‐population of CD8+ T cells. NKG2D engagement with its ligands directly activates NK cells and acts as a co‐stimulator on CD8+ T cells. Recent reports, however, have demonstrated a role for NKG2D in direct T‐cell activation in chronic inflammation. The aim of this study was to investigate the pattern of expression and the functional role of NKG2D on circulating and intrahepatic CD8+ T cells in chronic viral hepatitis. Peripheral blood lymphocytes and intrahepatic lymphocytes from 45 patients with chronic viral hepatitis (HBV and HCV) were studied. Phenotypic NKG2D expression and its functional ability to activate intrahepatic and circulating lymphocytes were analysed. Intrahepatic CD8+ T cells display increased NKG2D expression in chronic viral hepatitis in comparison with circulating CD8+ T cells. NKG2D co‐stimulates intrahepatic CD8+ T cells and hepatitis B virus‐specific CD8+ T cells. However, we could not demonstrate an ability to directly activate CD8+ T cells through the NKG2D signalling pathway alone. NKG2D is up‐regulated on intrahepatic CD8+ T cells in type B and C chronic viral hepatitis; however, its function appears to be restricted to that of a co‐stimulatory molecule.     

Adaptive response in hepatitis B virus infection

Hepatitis B virus (HBV) is a major cause of acute and chronic liver inflammation worldwide. The immune response against the virus represents a key factor in determining infection outcome, in terms of both viral clearance and the perpetuation of liver damage. Significant advances have recently been achieved regarding the functions of antiviral CD8+ T cells, leading to a better understanding of their abnormalities during chronic infection as well as the pathways to be manipulated to reverse the immune impairment of chronic infection. In this review, we aimed to analyse the patterns of adaptive immunity that develop during acute infection and the profiles in chronic infection. In addition to CD8+ T cells, which are the best‐described subset to date, we reviewed and commented on the direct and indirect roles of CD4+ T cells and B cells.     

Immune responses in hepatitis B virus infection

Hepatitis B virus infection is one of the most frequent causes of chronic liver disease worldwide. Even though a preventive vaccine is available, the search for a cure for chronically infected patients remains a high priority to reduce the morbidity and mortality from liver cirrhosis and hepatocellular carcinoma. This review summarizes the immune response in acute, self-limited and chronic hepatitis B; its differential effects on viral replication and liver injury; and prospects for immunotherapy.     

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.     

Viral hepatitis: virus/host interaction

Abstract   Hepatitis A virus is considered directly cytopathic to the liver cell. Severity of the liver damage is dictated by viral load. Acute infection is followed by sustained immunity to the virus. Hepatitis B (HBV) and C (HCV) viruses are noncytopathic, hepatotropic viruses that cause acute and chronic hepatitis and hepatoma. Cellular and humoral immune responses are responsible not only for viral clearance but also for hepatocyte damage. T-cell response to HBV is vigorous, polyclonal, and multispecific in acutely infected patients who clear the virus while it is weak and narrowly focused in chronically infected patients. It is mainly executed by cytotoxic T lymphocytes (CTL), which destroy infected hepatocytes and secrete antiviral cytokines that interrupt the HBV life cycle. T-cell response to HCV is strong and multispecific in both acutely and chronically infected patients. Whether HCV is susceptible to a cytokine-mediated type of control is unknown. The ability of HCV to persist despite a strong CTL response suggests that HCV is either less visible to the CTL or less responsive to cytokine-mediated antiviral signals than HBV. Both viruses, but especially HCV, have a high mutation rate, leading to the occurrence of variant viral genomes with growth advantage and the ability of escaping immune recognition.     

Simultaneously acute hepatitis B virus and C virus coinfection and subsequent chronic hepatitis C

Hepatitis C virus (HCV) and hepatitis B virus (HBV) share similar transmission routes, but concurrent acute HCV and HBV infection was rarely reported. Little is known about viral interaction and hepatic biochemical features of acute HBV and HCV coinfection. We report an intravenous drug abuser with simultaneous acute HBV and HCV infections presenting as biphasic elevation of both alanine aminotransferase (ALT) and total bilirubin levels. HCV infection is the major cause of continuing hepatitis after termination of HBsAg antigenemia.     

T cell immunopathogenesis and immunotherapeutic strategies for chronic hepatitis B virus infection

Hepatitis B is caused by the host immune response and T cells play a major role in the immunopathogenesis. More importantly, T cells not only destroy hepatocytes infected by hepatitis B virus (HBV), but also control HBV replication or eradicate HBV in a noncytolytic manner. Therefore, analysis of T cell immune response during acute and chronic HBV infection is important to develop a strategy for successful viral control, which could lead to immunotherapy for terminating persistent HBV infection. There have been many attempts at immunotherapy for chronic HBV infection, and some have shown promising results. High viral load has been shown to suppress antiviral immune responses and immunoinhibitory signals have been recently elucidated, therefore, viral suppression by nucleos(t)ide analogs, stimulation of antiviral immune response, and suppression of the immunoinhibitory signals must be combined to achieve desirable antiviral effects.     

Hepatitis B virus and hepatitis D virus replication in HBsAg-positive fulminant hepatitis

Hepatitis B virus DNA and hepatitis D virus RNA, the most sensitive markers of hepatitis B and hepatitis D virus replication, were sought by molecular hybridization with radioactive probes in serial serum samples from 29 consecutive patients with HBsAg-positive fulminant hepatitis. Nineteen patients had evidence of hepatitis D virus infection, as assessed by the presence in serum of delta antigen, anti-delta antibodies, or both. Hepatitis B virus DNA was found in only two patients: one was a chronic HBsAg carrier with hepatitis D virus superinfection and the other had fulminant hepatitis caused by hepatitis B and hepatitis D coinfection. Hepatitis D virus RNA was detected in three patients: two with hepatitis B and hepatitis D coinfection and also in the HBsAg carrier with positive hepatitis B virus DNA and hepatitis D virus superinfection. None of 10 patients with hepatitis B virus infection alone had detectable viral nucleic acids in serum. Overall, viral nucleic acids were detected in the sera of 4 of the 29 patients (14%). Hepatitis D virus antigenemia did not indicate hepatitis D virus replication because hepatitis D virus RNA was not detected in 9 of 12 patients with hepatitis D virus antigen in their sera. The low frequency of viral replication found in fulminant hepatitis B or D may explain the low recurrence rate of viral hepatitis in patients with fulminant hepatitis who have received liver transplantations.