HBV hepatitis mutations

Chronic infection of the liver by the hepatitis B virus (HBV) is associated with increased risk for developing hepatocellular carcinoma (HCC). A multitude of studies have investigated the mechanism of liver cancer pathogenesis due to chronic HBV infection. Chronic inflammation, expression of specific viral proteins such as HBx, the integration site of the viral genome into the host genome, and the viral genotype, are key players contributing to HCC pathogenesis. In addition, the genetic background of the host and exposure to environmental carcinogens are also predisposing parameters in hepatocarcinogenesis. Despite the plethora of studies, the molecular mechanism of HCC pathogenesis remains incompletely understood. In this review, the focus is on epigenetic mechanisms involved in the pathogenesis of HBV-associated HCC. Epigenetic mechanisms are dynamic molecular processes that regulate gene expression without altering the host DNA, acting by modifying the host chromatin structure via covalent post-translational histone modifications, changing the DNA methylation status, expression of non-coding RNAs such as microRNAs and long noncoding RNAs, and altering the spatial, 3-D organization of the chromatin of the virus-infected cell. Herein, studies are described that provide evidence in support of deregulation of epigenetic mechanisms in the HBV-infected/-replicating hepatocyte and their contribution to hepatocyte transformation. In contrast to genetic mutations which are permanent, epigenetic alterations are dynamic and reversible. Accordingly, the identification of essential molecular epigenetic targets involved in HBV-mediated HCC pathogenesis offers the opportunity for the design and development of novel epigenetic therapeutic approaches.

Aim: Genetic polymorphisms of human leukocyte antigen (HLA) class II molecules are associated with chronic hepatitis B virus (HBV) infection. We aimed to investigate the impacts of HLA-II haplotypes on viral evolution and the risks of HBV-caused liver diseases. Methods: HLA-DR-DQ-DP haplotypes were estimated in 1210 healthy controls, 296 HBV clearance subjects, 301 asymptomatic hepatitis B surface antigen carriers, 770 chronic hepatitis B patients, 443 HBV-related liver cirrhosis (LC) patients, and 1037 HBV-related hepatocellular carcinoma (HCC) patients. HBV mutations were determined by sequencing. The associations of HLA-DR-DQ-DP haplotypes with viral mutations and the risks of liver diseases were assessed by multivariate logistic regression. associated with decreased HCC risk, with an odds ratio (OR) [95% confidence interval (CI)] of 0.62 (0.40-0.95), 0.60 (0.39-0.92), 0.73 (0.54-0.98), and 0.58 (0.42-0.78), respectively. CCAACG, CCGACG, and TCAATA were significantly associated with decreased frequencies of the HCC-risk HBV mutations: preS1 deletion, APOBECsignature HBV mutations in the core promoter and preS regions, A51C/T, G104C/T, and G146C/T. TCGATA and TTAACG were associated with increased LC risk, with an OR (95%CI) of 1.54 (1.03-2.30) and 2.23 (1.50-3.33), respectively. However, TCGATA and TTAACG were not consistently associated with the cirrhosis-risk HBV mutations. Conclusion: CCAACG, CCGACG, and TCAATA are inversely associated with HCC risk, possibly because they are involved in creating an immune microenvironment attenuating the generation of HCC-risk HBV mutations. TCGATA and TTAACG might predispose the polarity of immunity towards Th17 isotype related to LC.

Introduction Lamivudine is an oral nucleoside analog that inhibits the replication of Hepatitis B Virus (HBV) by interfering with HBV reverse transcriptase activity. It is used to treat patients with Chronic Hepatitis B Virus (CHB) infection by decreasing the HBV-DNA viral load and Alanine Aminotransferase (ALT) levels as well as improving liver histology [1]. However, the emergence of lamivudine-resistant HBV strains in patients on long-term lamivudine-therapy has been reported at a rate of 14-32% after 1 year, increasing to 40%, 53% and 76% after 2, 3 and 4 years of continuous therapy, respectively [2]. Lamivudine-resistant mutants have also been reported in untreated asymptomatic carriers and in CHB patients [3-5]. Such resistant viruses exhibit characteristic mutations at positions rt204 (rtM204V: YVDD, rtM204I: YIDD and rtM204S: YSDD) and rt180 (rtL180M) in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the reverse transcriptase domain of the polymerase gene [6]. These mutations result in the re-elevation of HBV-DNA known as viral breakthrough and rising ALT levels known as biochemical breakthrough [7]. Given the loss of therapeutic efficacy associated with the development of resistance to lamivudine and the availability of new Abstract Introduction: Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication via suppression of the RNA-dependent DNA polymerase. However, patients with prolonged therapy were previously detected harboring drug-resistant mutants. Such mutants though partially replication defective, confer resistance to lamivudine and can elicit exacerbation of hepatonecro-inflammation.