Dandri M, Locarnini S. New insight in the pathobiology of hepatitis B virus infection

Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr 52, D-20246, Hamburg, Germany.
Gut (Impact Factor: 14.66). 05/2012; 61 Suppl 1(Suppl 1):i6-17. DOI: 10.1136/gutjnl-2012-302056
Source: PubMed


Chronic hepatitis B virus (HBV) infection remains a major health burden and the main risk factor for the development of hepatocellular carcinoma worldwide. However, HBV is not directly cytopathic and liver injury appears to be mostly caused by repeated attempts of the host's immune responses to control the infection. Recent studies have shown that the unique replication strategy adopted by HBV enables it to survive within the infected hepatocyte while complex virus-host interplays ensure the virus is able to fulfil its replication requirements yet is still able to evade important host antiviral innate immune responses. Clearer understanding of the host and viral mechanisms affecting HBV replication and persistence is necessary to design more effective therapeutic strategies aimed at improving the management of patients with chronic HBV infection to eventually achieve viral eradication. This article focuses on summarising the current knowledge of factors influencing the course of HBV infection, giving emphasis on the use of novel assays and quantitative serological and intrahepatic biomarkers as tools for predicting treatment response and disease progression.

59 Reads
  • Source
    • "Over the past two decades, major advances have been made in the treatment of chronic HBV infection, but complete and sustained viral eradication is difficult to achieve with the currently available treatments (Tang et al., 2014; Wong and Chan, 2013). Preclinical and clinical studies have indicated the necessity of stimulating HBV-specific B cell and T cell responses to bring about long-term viral control in chronically infected patients (Bertoletti and Ferrari, 2012; Dandri and Locarnini, 2012; Grimm et al., 2013; Kosinska et al., 2015), and several reviews have summarized recent therapeutic approaches that have been attempted to achieve this control (Kosinska et al., 2015; Liu et al., 2014a,b; Marimani et al., 2013; Michel et al., 2015, 2011; Wang et al., 2014; Zhang et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: CpG oligodeoxynucleotides (ODNs) stimulate immune cells via TLR9 and are potentially useful immunomodulators for the treatment of chronic viral infections. In the present study, different classes of CpGs were tested for their capacities for innate immune activation and antiviral activities in the woodchuck model. A class P CpG ODN was found to stimulate interferon (IFN) production in woodchuck peripheral blood mononuclear cells (PBMCs) in vitro, and following subcutaneous administration in vivo, it was observed to induce IFN and MxA expression in woodchuck PBMCs. Combination treatment with CpG ODN and entecavir (ETV) led to effective suppression of the woodchuck hepatitis virus (WHV) load in the woodchucks, with early viral responses and inhibition of replication. The woodchuck hepatitis surface antigen (WHsAg) serum concentrations were strongly decreased by CpG and ETV together but not by either agent alone, indicating synergistic effects. However, viral control post-treatment was still transient, similar to that observed with ETV alone. Significantly elevated levels of serum aspartate aminotransferase (AST) but not of alanine aminotransferase (ALT) in some of the woodchucks receiving CpG ODN were noted, but these increases were resolved before the completion of treatment and were not associated with an elevated serum bilirubin level or coagulation disorders, suggesting the absence of a significant safety concern.
    Antiviral research 11/2015; DOI:10.1016/j.antiviral.2015.11.001 · 3.94 Impact Factor
  • Source
    • "In this respect, some other data suggest that, during chronic infection, HBV could negatively regulate host immune responses by interfering with TLR expression and signaling pathways [12] [13] [14], or by inhibiting interferon (IFN) response [15] [16] [17] [18] [19]. Underlying molecular mechanisms could involve several distinct HBV proteins as recently reviewed [2] [5] [6]. However to date, there are no very early kinetic interaction study between HBV and hepatocytes that have been performed to determine if the virus could; i) be initially detected by host cells; ii) modulate host immune gene expression; and then iii) inhibit innate responses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The outcome of Hepatitis B virus infection may be influenced by early interactions between the virus and hepatocyte innate immune responses. To date, the study of such interactions during the very early step of infection has not been adequately investigated. We used the HepaRG cell line, as well as primary human hepatocytes to analyze, within 24 hours of exposure to HBV, either delivered by a physiologic route or baculovirus vector (Bac-HBV), the early modulation of the expression of selected antiviral/pro-inflammatory cytokines and interferon-stimulated-genes. Experiments were also performed in presence or absence of innate receptor agonists to investigate early HBV-induced blockade of innate responses. We show that hepatocytes themselves could detect HBV, and express innate genes when exposed to either HBV virions or Bac-HBV. Whereas Bac-HBV triggered a strong antiviral cytokine secretion followed by the clearance of replicative intermediates, a physiologic HBV exposure led to an abortive response. The early inhibition of innate response by HBV was mainly evidenced on TLR3 and RIG-I/MDA5 signaling pathways upon engagement with exogenous agonist, leading to a decreased expression of several pro-inflammatory and antiviral cytokine genes. Finally, we demonstrate that this early inhibition of dsRNA-mediated response is due to factor(s) present in the HBV inoculum, but not being HBsAg or HBeAg themselves, and does not require de novo viral protein synthesis and replication. Our data provide strong evidence that HBV viral particles themselves can readily inhibit host innate immune responses upon virion/cell interactions, and may explain, at least partially, the "stealthy" character of HBV. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 07/2015; DOI:10.1016/j.jhep.2015.07.014 · 11.34 Impact Factor
  • Source
    • "Epidemiologic data demonstrate that HBV is a risk factor in liver cancer development but little is known about the molecular mechanisms (Dandri and Locarnini, 2012). Although the virus is not directly cytopathic, liver injuries are produced due to the repeated attempts of the host's immune response to control the infection (Dandri and Locarnini, 2012). Furthermore, experimental evidence has shown that various receptors encoded by the major histocompatibility complex (MHC) play an important role in the antigen presentation to cytotoxic T cells, which are decisive for the HBV infected hepatocytes destruction (Zhou et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The major histocompatibility complex (MHC)-containing genes are among the most polymorphic in vertebrates. MHC genes code for proteins that are critical in the immune system response. In this study, the polymorphism of the second exon of the MHC class II DRB gene was characterized in the Eastern woodchuck (Marmota monax). Woodchucks chronically infected with the woodchuck hepatitis virus (WHV) represent the best available animal model for the study of chronic hepatitis B infection in humans. In the genotyped animals we found fifteen alleles, which were expressed in two independent loci and that were named DRB1A and DRB1B in this work. The 15 alleles investigated showed an elevated divergence. A significant excess of non-synonymous substitutions was detected, which could indicate that a historical positive selection is acting in the woodchuck DRB1 genes. This hypothesis was confirmed in our study by the high variability in or near the antigen binding sites (ABS) and by the results obtained in sequence variability analyses. This analysis identified the presence of a microsatellite sequence that is located at the start of the second intron, which could further allow the development of a fast and cheap semiautomatic sequencing method.
    Molecular Immunology 10/2014; 63(2). DOI:10.1016/j.molimm.2014.10.011 · 2.97 Impact Factor
Show more