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.
"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.
"The degradation is complete except for its 5' terminal, 15–18 nucleotides which serve as a primer for plusstrand DNA synthesis resulting in rcDNA formation [Beck and Nassal, 2007; Nassal, 2008]. Mature capsids containing rcDNA can be either recycled for intracellular cccDNA amplification [Tuttleman et al., 1986; Locarnini and Mason, 2006], or assembled with viral surface proteins in the endoplasmic reticulum to form progeny viral particles that will be released from the cell [Ganem, 1991; Locarnini and Zoulim, 2010; Dandri and Locarnini, 2012]. "
"On the basis of HBV antibody proﬁle, OHBS may be distinguished as: seropositive-OHBS (anti-HBc and/or anti-HBs positive) and Seronegative-OHBS (anti-HBc and anti-HBs negative) (4).The clinical relevance of OHBS has not been investigated extensively; however, several studies have suggested a potential association between OHBS and increased risk of cirrhosis and hepatocellular carcinoma (HCC). In addition, it can be transmitted throughliver transplantation or blood transfusion (2, 5, 6). "
[Show abstract][Hide abstract] ABSTRACT: Occult hepatitis B virus (HBV) status (OHBS) is simply defined as the presence of HBV DNA in the liver (with or without detectable HBV DNA in the serum), in the absence of serum HBV surface antigen (HBsAg). Importance of OHBS is mostly clinical, related to its possible role in spreading through blood transfusion and liver transplantation; causing classic forms of HBV. Mechanisms underlying this entity are poorly defined. Several possibilities have been suggested, with major classification into two groups: defective host immune response and viral replication activity through mutations of HBV DNA sequence. Mutations are extensively investigated in all four overlapping open reading frames (ORFs) of HBV genome, to define their possible role in the pathogenesis of OHBS. Some of these mutations like S-escape mutants could not be detected by the routine available assays, making them difficult to diagnosis. Therefore, trying to detect this covert condition could be more helpful for defining better preventive and therapeutic strategies.
In the present study we provided an in-depth review of the most important new data available on different mutations in HBV genome of patients with OHBS, which may play a role in the pathogenesis of OHBS. The data were collected through reviewing the full-text articles, identified by the PubMed search, using the following keywords and their different combinations: occult hepatitis B, HBV genome, "a" determinant, HBV open reading frames, S mutations, X mutations, P mutations and C mutations.
Variants within the major hydrophilic region (MHR) of the HBsAg, deletions in the pre-S1region, codon stop in the S open reading frames (ORF), sporadic non common mutations, some mutations affecting the posttranslational production of HBV proteins in the S ORF like deletion mutations, mutations in start codon and nucleotide changes in the X ORF, deletion and point mutations in P ORF and sometimes, nucleotide substitution in the C ORF are among the assumed mutations detected to have a role in OHBS appearance.
Studies mostly lacked a control group and the whole-length HBV sequencing was scant with conflicting results, suggesting that OHBS is often a result of multiple mechanisms. Additional studies on full-length HBV genomes from occult and non-occult HBV cases may shed more light on the interplay between different mechanisms involved in the pathogenesis of OHBS.
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