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.     

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.     

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.     

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.     

The influence of the human genome on chronic viral hepatitis outcome

The mechanisms that determine viral clearance or viral persistence in chronic viral hepatitis have yet to be identified. Recent advances in molecular genetics have permitted the detection of variations in immune response, often associated with polymorphism in the human genome. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virulence of microbial agents. Several recent advances concerning the influence of human genes in chronic viral hepatitis B and C are discussed in this article: a) the associations between human leukocyte antigen polymorphism and viral hepatic disease susceptibility or resistance; b) protective alleles influencing hepatitis B virus (HBV) and hepatitis C virus (HCV) evolution; c) prejudicial alleles influencing HBV and HCV; d) candidate genes associated with HBV and HCV evolution; d) other genetic factors that may contribute to chronic hepatitis C evolution (genes influencing hepatic stellate cells, TGF-beta 1 and TNF-alpha production, hepatic iron deposits and angiotensin II production, among others). Recent discoveries regarding genetic associations with chronic viral hepatitis may provide clues to understanding the development of end-stage complications such as cirrhosis or hepatocellular carcinoma. In the near future, analysis of the human genome will allow the elucidation of both the natural course of viral hepatitis and its response to therapy.     

Human hepatitis viruses-associated cutaneous and systemic vasculitis

Human hepatitis viruses (HHVs) include hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus, and hepatitis E virus and can cause liver inflammation in their common human host. Usually, HHV is rapidly cleared by the immune system, following acute HHV invasion. The morbidities associated with hepatitis A virus and hepatitis E virus infection occur shortly after their intrusion, in the acute stage. Nevertheless, the viral infectious process can persist for a long period of time, especially in HBV and HCV infection, leading to chronic hepatitis and further progressing to hepatic cirrhosis and liver cancer. HHV infection brings about complications in other organs, and both acute and chronic hepatitis have been associated with clinical presentations outside the liver. Vascular involvement with cutaneous and systemic vasculitis is a well-known extrahepatic presentation; moreover, there is growing evidence for a possible causal relationship between viral pathogens and vasculitis. Except for hepatitis delta virus, other HHVs have participated in the etiopathogenesis of cutaneous and systemic vasculitis via different mechanisms, including direct viral invasion of vascular endothelial cells, immune complex-mediated vessel wall damage, and autoimmune responses with stimulation of autoreactive B-cells and impaired regulatory T-cells. Cryoglobulinemic vasculitis and polyarteritis nodosa are recognized for their association with chronic HHV infection. Although therapeutic guidelines for HHV-associated vasculitis have not yet been established, antiviral therapy should be initiated in HBV and HCV-related systemic vasculitis in addition to the use of corticosteroids. Plasma exchange and/or combined cyclophosphamide and corticosteroid therapy can be considered in patients with severe life-threatening vasculitis manifestations.     

A Review of Hepatitis B Virus and Hepatitis C Virus Immunopathogenesis

Despite the advances in therapy, hepatitis B virus (HBV) and hepatitis C virus (HCV) still represent a significant global health burden, both as major causes of cirrhosis, hepatocellular carcinoma, and death worldwide. HBV is capable of incorporating its covalently closed circular DNA into the host cell’s hepatocyte genome, making it rather difficult to eradicate its chronic stage. Successful viral clearance depends on the complex interactions between the virus and host’s innate and adaptive immune response. One encouraging fact on hepatitis B is the development and effective distribution of the HBV vaccine. This has significantly reduced the spread of this virus. HCV is a RNA virus with high mutagenic capacity, thus enabling it to evade the immune system and have a high rate of chronic progression. High levels of HCV heterogeneity and its mutagenic capacity have made it difficult to create an effective vaccine. The recent advent of direct acting antivirals has ushered in a new era in hepatitis C therapy. Sustained virologic response is achieved with DAAs in 85–99% of cases. However, this still leads to a large population of treatment failures, so further advances in therapy are still needed. This article reviews the immunopathogenesis of HBV and HCV, their properties contributing to host immune system avoidance, chronic disease progression, vaccine efficacy and limitations, as well as treatment options and common pitfalls of said therapy.     

Hepatitis B and hepatitis C viruses: a review of viral genomes,viral induced host immune responses,genotypic distributions and worldwide epidemiology

Hepatitis B and hepatitis C viruses (HCV) are frequently propagating blood borne pathogens in global community. Viral hepatitis is primarily associated with severe health complications, such as liver cirrhosis, hepatocellular carcinoma, hepatic fibrosis and steatosis. A literature review was conducted on hepatitis B virus (HBV), HBV genome, genotypic distribution and global epidemiology of HBV, HCV, HCV genome, HCV and host immune responses, HCV genotypic distribution and global epidemiology. The valued information was subjected for review. HBV has strict tissue tropism to liver. The virus infecting hepatocytes produces large amount of hepatitis B surface antigen particles which lack the DNA. It has capability to integrate into host genome. It has been found that genotype C is most emerging genotype associated with more severe liver diseases (cirrhosis). The approximate prevalence rate of genotype C is 27.7% which represents a major threat to future generations. Approximately 8% of population is chronic carrier of HBV in developing countries. The chronic carrier rate of HBV is 2%-7% in Middle East, Eastern and Southern Europe, South America and Japan. Among HCV infected individuals, 15% usually have natural tendency to overcome acute viral infection, where as 85% of individuals were unable to control HCV infection. The internal ribosomal entry site contains highly conserved structures important for binding and appropriate positioning of viral genome inside the host cell. HCV infects only in 1%-10% of hepatocytes, but production of tumor necrosis factor alpha (from CD8+ cells) and interferon-gamma cause destruction of both infected cells and non-infected surrounding cells. Almost 11 genotypes and above 100 subtypes of HCV exists worldwide with different geographical distribution. Many efforts are still needed to minimize global burden of these infections. For the complete eradication of HBV (just like small pox and polio) via vaccination strategies, sincere efforts would be required from government and nongovernmental organizations.     

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.     

持续性HBV或HCV感染与免疫稳态

机体与病毒相互作用维持稳态是一种自然属性。免疫系统一方面需要活化免疫应答作用,杀灭或清除病毒;另一方面要调控免疫应答不要过度,维持免疫系统的稳定状态。持续性肝炎病毒感染(如HBV、HCV)的原因是病毒分子成分损害机体免疫系统并发生变异逃逸免疫清除。机体与病毒长期共存是多种免疫细胞和分子参与的过程,是机体在抗病毒免疫应答过程中维持自身稳态的结果。对持续肝炎病毒感染过程中机体维持相对稳定状态的细胞与分子机制作一综述。     

Clinical impact of hepatitis B and C virus envelope glycoproteins

Chronic infection by either hepatitis B virus(HBV)or hepatitis C virus(HCV)share epidemiological characteristics with risks for development of severe complications such as liver cirrhosis and hepatocellular carcinoma.HBV and HCV also share a high genetic variability. Among highly variable regions,viral genes encoding surface proteins(hepatitis B surface antigen,E1/E2 HCV glycoproteins)play key roles in the stimulation of the host-related immune response and viral entry into hepatocytes.Specific segments of HBV envelope proteins(preS1,"a"determinant)are crucial in the entry process into permissive cells.HCV entry is a complex multistep process involving multiple cell cofactors (glycosaminoglycans,low density lipoprotein receptor, SR-B1,CD81,claudin-1,occludin,EGFR,EphA2)in the interaction with HCV E1/E2 envelope glycoproteins.In vitro both viruses can be controlled by antibody-me-diated neutralization targeting viral envelope,also essential in preventing HBV infection in vivo as observed through successful vaccination using HBs antigen.But preventive vaccination and/or therapeutic pressure can influence HBV and HCV variability.For HBV,the patterns of antiviral drug resistance in chronic hepatitis are complex and the original pol/S gene overlap has to be taken into account.Treatment-induced HBV mutations in pol could indeed generate S mutants with subsequent modified antigenicity or increased cancer induction.Variability of HBV and HCV envelope proteins combining high exposure to selective pressures and crucial functional roles require investigation in the context of diagnostic,vaccination and treatment tools.In this editorial a synthesis is performed of HBV and HCV envelope properties at the entry step and as antigenic proteins,and the subsequent clinical impact.     

Hepatitis C virus eradication associated with hepatitis B virus superinfection and development of a hepatitis B virus specific T cell response

BACKGROUND/AIMS: Specific T cell responses during acute hepatitis B and during chronic hepatitis C have been described in detail. However, the T cell responses during the rare setting of acute hepatitis B virus (HBV) infection in the course of chronic hepatitis C that eventually lead to clearance of both viruses are completely unknown. METHODS: We analyzed the virus specific CD4+ and CD8+ T cell response during an acute HBV superinfection in a patient with chronic hepatitis C. RESULTS: The patient eliminated hepatitis C virus (HCV)-RNA and HBV-DNA from serum soon after the clinical onset of acute hepatitis B. The HBV specific T cell response found in this patient corresponds to the typical response that has been described in acute hepatitis B without chronic HCV infection. In contrast the hepatitis C specific immune response was similar to that generally found in chronic hepatitis C despite the fact that the patient also eliminated HCV-RNA. CONCLUSIONS: We hypothesize that the acute HBV infection induced a HBV specific T cell response which was associated with elimination HBV DNA and HCV-RNA, the latter possibly by bystander mechanisms, e.g. via secretion of cytokines. If such a non-specific bystander mechanism which has proven to be effective in the experimental setting and which is formally described here for a single patient can be shown to be a more general phenomenon, it may support the approach with new antiviral strategies, e.g. the induction of non-specific defense mechanisms against HCV.     

Viral hepatitis: Innovations and expectations

Viral hepatitis is a significant health problem worldwide,associated with morbidity and mortality.Hepatitis B,C,D,and occasionally E viruses(HBV,HCV,HDV,and HEV)can evolve in chronic infections,whereas hepatitis A virus(HAV)frequently produces acute self-limiting hepatitis.In the last years,different studies have been performed to introduce new antiviral therapies.The most important goal in the treatment of viral hepatitis is to avoid chronic liver disease and complications.This review analyzes currently available therapies,in particular for viruses associated with chronic liver disease.The focus is especially on HBV and HCV therapies,investigating new drugs already introduced in clinical practice and clinical trials.We also describe new entry inhibitors,developed for the treatment of chronic HDV and HBV and currently available treatments for HEV.The last drugs introduced have shown important efficacy in HCV,with achievable target HCV elimination by 2030.Concurrently,renewed interest in curative HBV therapies has been registered;current nucleotide/nucleoside analogs positively impact liver-related complications,ensuring high safety and tolerability.Novel approaches to HBV cure are based on new antivirals,targeting different steps of the HBV life cycle and immune modulators.The improved knowledge of the HDV life cycle has facilitated the development of some direct-acting agents,as bulevirtide,the first drug conditionally approved in Europe for HDV associated compensated liver disease.Further studies are required to identify a new therapeutic approach in hepatitis E,especially in immunosuppressed patients.     

Genetic diversity of hepatitis viruses in West-African countries from 1996 to 2018

The severity of hepatic pathology and the response to treatment depend on the hepatitis virus genotype in the infected host. The objective of this review was to determine the distribution of hepatitis virus genotypes in West African countries. A systematic review of the literature in PubMed, Google Scholar and Science Direct was performed to identify 52 relevant articles reporting hepatitis A, B, C, D, E and G viruses genotypes. Hepatitis B virus (HBV) genotype E with a prevalence of 90.6% (95%CI: 0.891-0.920) found in this review, is characterized by low genetic diversity. Hepatitis C virus (HCV) genotypes 1 and 2 represented 96.4% of HCV infections in West African countries, while hepatitis delta virus, hepatitis A virus, hepatitis G virus genotypes 1 and HEV genotype 3 were reported in some studies in Ghana and Nigeria. HBV genotype E is characterized by high prevalence, low genetic diversity and wide geographical distribution. Further studies on the clinical implications of HBV genotype E and HCV genotypes 1 and 2 are needed for the development of an effective treatment against this viral hepatitis in West African countries. Surveillance of the distribution of different genotypes is also needed to reduce recombination rates and prevent the emergence of more virulent viral strains.     

Revisiting the Natural History of Chronic HBV Infection

Although effective vaccines have been available for more than three decades, hepatitis B virus (HBV) infection remains a global public health issue. It is estimated around 248 million people are chronically infected by HBV, and most of them are residing in the Asia-Pacific region. In HBV-endemic regions, the virus is primarily transmitted during the perinatal period or early childhood with an immature immune system, so it has a high rate of chronicity. Based on the virological and clinical manifestations, the natural course of chronic hepatitis B can be divided into four classical phases: immune tolerance, immune clearance, inactive carrier, and reactivation phases. The majority of patients will undergo spontaneous HBeAg seroconversion and enter an inactive carrier state. However, a small portion of patients may encounter intermittent or persistent hepatitis and eventually lead to severe adverse outcomes, such as liver cirrhosis, hepatic failure, or hepatocellular carcinoma. With recent advances in molecular and immunological technologies, several viral and host factors that may affect the clinical outcomes of chronic HBV infection have been identified. By integration of these emerging serological and viral biomarkers, the natural history of chronic HBV infection should be revisited. In conclusion, accurate definition of the natural history of chronic HBV infection not only sheds light on the pathogenesis of chronic hepatitis B but also helps determine the optimal timing for antiviral therapy to cure HBV.     

Innate and adaptive immune escape mechanisms of hepatitis B virus

Chronic hepatitis B virus (HBV) infection is an international health problem with extremely high mortality and morbidity rates. Although current clinical chronic hepatitis B (CHB) treatment strategies can partly inhibit and eliminate HBV, viral breakthrough may result due to non-adherence to treatment, the emergence of viral resistance, and a long treatment cycle. Persistent CHB infection arises as a consequence of complex interactions between the virus and the host innate and adaptive immune systems. Therefore, understanding the immune escape mechanisms involved in persistent HBV infection is important for designing novel CHB treatment strategies to clear HBV and achieve long-lasting immune control. This review details the immunological and biological characteristics and escape mechanisms of HBV and the novel immune-based therapies that are currently used for treating HBV.     

Current status and prospects of studies on human genetic alleles associated with hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection can cause a broad spectrum diseases, including from asymptomatic HBV carriers or cryptic hepatitis, to acute hepatitis, chronic hepatitis, Liver cirrhosis and primary hepatocellular carcinoma. The variable pattern and clinical outcome of the infection were mainly determined by virological itself factors, host immunological factors and genetic factors as well as the experimental factors. Among the human genetic factors, major candidate or identified genes involved in the process of HBV infection fall into the following categories: (1) genes that mediate the processes of viral entry into hepatocytes, including genes involved in viral binding, fusion with cellular membrane and transportation in target cells; (2) genes that modulate or control the immune response to HBV infection; (3) genes that participate in the pathological alterations in liver tissue;(4) genes involved in the development of liver cirrhosis and hepatocellular carcinoma associated with chronic HBV infection, including genes related to mother-to-infant transmission of HBV infection; and (5) those that contribute to resistance to antiviral therapies. Most of the reports of human genes associated with HBV infection have currently focused on HLA associations. For example, some investigators reported the association of the HLA class Ⅱ alleles such as DRB1^*1302 or HLA-DR13 or DQA1^*0501-DQB1^*0301-DQB1^*1102 haplotypes with acute and/or chronic hepatitis B virus infection, respectively. Several pro-inflammatory cytokines such as Th1 cytokines (including IL-2 and IFN-γ)and TNF-α have been identified to participate the process of viral clearance and host immune response to HBV. In contrast, the Th2 cytokine IL-10 serves as a potent inhibitor of Th1 effector cells in HBV diseases. The MBP polymorphisms in its encoding region were found to be involved in chronic infection. Thus, reports from various laboratories have shown some inconsistencies with regard to the effects of host genetic factors on HBV clearance and persistence. Since genetic interactions are complex, it is unlikely that a single allelic variant is responsible for HBV resistance or susceptibility. However, the collective influence of several single nucleotide polymorphisms (SNPs) or haplotype (s)may underlie the natural combinational or synergistic protection against HBV. The future study including the multicohort collaboration will be needed to clarify these preliminary associations and identify other potential candidate genes.The ongoing study of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HBV infection, but may also providea novel rationale for new methods of diagnosis and therapeutic strategies.     

Dual chronic hepatitis B virus and hepatitis C virus infection

Dual hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are common in HBV or HCV endemic areas. However, several clinical and pathogenetic issues remain unresolved. First, clinical and in vitro studies suggest the interactions between two viruses. The dynamics of the interaction in untreated setting versus treated setting and its influence on the long-term outcomes await further studies. A key issue regarding viral interactions is whether modulation of infection occurs in the same dually infected individual hepatocyte of the liver. Clarifying this issue may help to understand the reciprocal interference between HCV and HBV and provide clues for future immunopathogenetic studies. Second, the prevalence and clinical significance of coexisting occult HBV infection in patients with chronic HCV infection need further investigations. Third, combination therapy of peginterferon alfa-2a and ribavirin appears to be just as effective and safe for the treatment of hepatitis B surface antigen (HBsAg)-positive patients chronically infected with active chronic hepatitis C as it is in patients with HCV monoinfection. Nevertheless, one-third of dually infected patients with nondetectable serum HBV DNA-level pretreatment developed HBV reactivation posttreatment. How to prevent and treat this reactivation should be clarified. Furthermore, about 10% of the dually infected patients lost HBsAg. Underlying mechanisms await further investigations. Finally, the optimal treatment strategies for dually infected patients with hepatitis B e antigen-positive chronic hepatitis B should be identified in future clinical trials.     

Adaptive Immune Responses,Immune Escape and Immune-Mediated Pathogenesis during HDV Infection

The hepatitis delta virus (HDV) is the smallest known human virus, yet it causes great harm to patients co-infected with hepatitis B virus (HBV). As a satellite virus of HBV, HDV requires the surface antigen of HBV (HBsAg) for sufficient viral packaging and spread. The special circumstance of co-infection, albeit only one partner depends on the other, raises many virological, immunological, and pathophysiological questions. In the last years, breakthroughs were made in understanding the adaptive immune response, in particular, virus-specific CD4+ and CD8+ T cells, in self-limited versus persistent HBV/HDV co-infection. Indeed, the mechanisms of CD8+ T cell failure in persistent HBV/HDV co-infection include viral escape and T cell exhaustion, and mimic those in other persistent human viral infections, such as hepatitis C virus (HCV), human immunodeficiency virus (HIV), and HBV mono-infection. However, compared to these larger viruses, the small HDV has perfectly adapted to evade recognition by CD8+ T cells restricted by common human leukocyte antigen (HLA) class I alleles. Furthermore, accelerated progression towards liver cirrhosis in persistent HBV/HDV co-infection was attributed to an increased immune-mediated pathology, either caused by innate pathways initiated by the interferon (IFN) system or triggered by misguided and dysfunctional T cells. These new insights into HDV-specific adaptive immunity will be discussed in this review and put into context with known well-described aspects in HBV, HCV, and HIV infections.     

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.