the SOCS5-mediated ubiquitination of the epidermal growth factor receptor (EGFR). These results demonstrate that HBV- miR-3 activates the innate immune response to restrain HBV replication by multiple pathways, which may suppress HBV-induced acute liver cell injury and affect the progression of persistent HBV infection.

HBV induced hepatocellular carcinoma and related potential immunotherapy Jia L, Gao Y, He Y, Hooper JD, Yang P. Pharmacol Res 2020; 159: 104992. doi: 10.1016/j.phrs.2020.104992.

Chronic infection by hepatitis B virus (HBV) has long been recognised as a major risk factor in the initiation and development of hepatocellular carcinoma (HCC), contributing to over half the cases of HCC worldwide. Transformation of the liver with HBV infection to HCC mainly results from long-term interaction between HBV and the host hepatocytes via a variety of mechanisms, including HBV DNA integration, prolonged expression of the viral HBx regulatory protein and/or aberrant preS/S envelope proteins, and epigenetic dysregulation of tumour suppressor genes. While there have been several failures in the development of drugs for HCC, the immune-tolerant microenvironment of this malignancy suggests that immunotherapeutic agents could provide benefits for these patients. This is supported by recent data showing that immunotherapy has promising activity in patients with advanced HCC. In this review, the authors provide an overview of HBV-induced HCC and recent immune-based approaches for the treatment of HCC patients.

Performance of the Xpert HBV Viral Load assay versus the Aptima Quant assay for quantifying hepatitis B virus DNA Abravanel F, Lhomme S, Trémeaux P et al. Diagn Microbiol Infect Dis 2020; 96 (2): 114946. doi: 10.1016/ j.diagmicrobio.2019.114946.

Quantification of HBV DNA is used for initiating and monitoring antiviral treatment. In the present study, the authors evaluated the Xpert HBV Viral Load (VL) assay on the GeneXpert instrument. They estimated its limit of detection to be 7.5 IU/mL. Reproducibility was 1.1–12.7% as assessed by the coefficients of variation for three different samples.

The assay was linear from 2 to 8 log10 IU/mL for HBV genotypes A to F. 60

Its clinical performance was evaluated by testing prospectively 100 HBV DNA- positive samples with the Xpert HBV VL and Aptima Quant HBV assays. The results from the two assays were correlated, with a modest bias (–0.10 log10 IU/mL) between them, by Bland-Altman analysis. Patient monitoring with 80 samples

performed with both assays gave similar patient profiles with trends in the same direction. The Xpert HBV Viral Load assay is sufficiently reliable for quantifying HBV DNA in clinical practice.

HBV variants are common in the ‘immune-tolerant’ phase of chronic hepatitis B Yuen L, Revill PA, Rosenberg G et al. J Viral Hepat 2020; 27 (10): 1061–70. doi: 10.1111/jvh.13318.

Nucleos(t)ide analogue (NUC) treatment prevents progression of liver fibrosis in subjects with chronic hepatitis B (CHB). However, risk of hepatocellular carcinoma (HCC) persists despite viral suppression. Specific HBV variants have been associated with adverse outcomes, including HCC; however, the frequency of these variants during the seemingly benign immunotolerant phase is unknown. Next-generation sequencing and detailed virological characterisation on a cohort of treatment-naïve immunotolerant subjects were performed to determine the frequency of clinically relevant viral variants. Samples from 97 subjects (genotype B/C 55%/45%, median HBV- DNA 8.5 log10 IU/mL, median HBsAg 4.8 log10 IU/mL, median HBeAg 3.6 log10 IU/mL) were analysed. Despite subjects being in the immunotolerant phase, clinically relevant HBV variants were common at baseline, particularly in the basal core promoter (BCP, overlaps the hepatitis B X [HBx] gene), precore and PreS regions. BCP/HBx variants were independently associated with lower baseline HBeAg, HBsAg and HBV-DNA titres. Precore variants were independently associated with higher baseline alanine transaminase (ALT). Increased viral diversity was associated with increased age and lower HBV-DNA, HBsAg and HBeAg levels. Low-level (<5%) drug resistance- associated amino acid substitutions in the HBV reverse transcriptase were detected in nine (9%) subjects at pre-treatment but were not associated with reduced antiviral activity.

The authors suggest that future studies should evaluate whether or not the detection of HBV variants during immunotolerant CHB is predictive of progression to immune clearance and poor prognosis, and if early initiation of

antiviral therapy during immunotolerant CHB to prevent the selection of HBV variants is clinically beneficial.

Hepatitis B virus-encoded microRNA (HBV-miR-3) regulates host gene PPM1A related to hepatocellular carcinoma Chavalit T, Nimsamer P, Sirivassanametha K et al. Microrna 2020; 9 (3): 232–9. doi: 10.2174/2211536608666191104105334.

Hepatitis B is a liver disease caused by the hepatitis B virus (HBV) that can become chronic and develop into hepatocellular carcinoma (HCC). HBV is classified as a double-stranded DNA virus, and currently it is reported that HBV virus-encoded miRNA (HBV-miR-3) controls the replication of HBV. However, the regulation of HBV-miR-3 in host cells remains unclear.

This study aimed to investigate the

regulation of HBV-miR-3 in host gene target related to chronic HBV infection and HCC process.

The authors analysed the read count

of HBV-miR-3 from next-generation sequencing (NGS) of chronic hepatitis patients on pegylated interferon-alpha-2a (PEG-IFNα-2a) treatment. To understand the regulation of HBV-miR-3 in host cells, the HBV-miR-3 recognition sites were predicted in host target genes using miRDB. The effect of HBV-miR-3 in host cells was examined using qPCR and 3’ UTR dual luciferase assay. The read count of HBV-miR-3 was found in chronic hepatitis patients before treatment. Moreover, the decrease of HBV-miR-3 was correlated with a response group of chronic hepatitis patients after treatment. The abundance of HBV-miR-3 showed no difference in the non-response group of chronic patients after PEG-IFNα- 2a treatment. To study the role of HBV-miR-3 in patients, four HBV-miR-3 target regions from protein phosphatase 1A (PPM1A) and DIX domain containing 1 (DIXDC1) were identified in the human genome using miRDB. The authors found that HBV-miR-3 hybridised with PPM1A mRNA. The mRNA expression from RT-qPCR showed no difference between HepG2 transfected with pSilencer scramble or pSilencer_HBV- miR-3. However, the reporter assay showed that PPM1A mRNA was suppressed by HBV-miR-3. The protein expression of PPM1A showed a decrease in cells over-expressing HBV-miR-3. This study is the first report to show

that HBV-encoded miRNA can regulate host gene expression. HBV-miR-3 silenced PPM1A by inhibiting the translation process of PPM1A. The down-regulation of PPM1A promotes cell proliferation related to HCC development.



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