2. Genomic Diversity of Hepatitis B Virus Infection Associated With Fulminant Hepatitis B Development
Context: After five decades of Hepatitis B Virus (HBV) vaccine discovery, HBV is still a major public health problem. Due to the high genetic diversity of HBV and selective pressure of the host immune system, intra-host evolution of this virus in different clinical manifestations is a hot topic of research. HBV infection causes a range of clinical manifestations from acute to chronic infection, cirrhosis and hepatocellular carcinoma. Among all forms of HBV infection manifestations, fulminant hepatitis B infection possesses the highest fatality rate. Almost 1% of the acutely infected patients develop fulminant hepatitis B, in which the mortality rate is around 70%.
Evidence Acquisition: All published papers deposited in Genbank, on the topic of fulminant hepatitis were reviewed and their virological aspects were investigated. In this review, we highlight the genomic diversity of HBV reported from patients with fulminant HBV infection.
Results: The most commonly detected diversities affect regulatory motifs of HBV in the core and S region, indicating that these alterations may convert the virus to an aggressive strain. Moreover, mutations at T-cell and B-cell epitopes located in pre-S1 and pre-S2 proteins may lead to an immune evasion of the virus, likely favoring a more severe clinical course of infection. Furthermore, point and frame shift mutations in the core region increase the viral replication of HBV and help virus to evade from immune system and guarantee its persistence.
Conclusions: Fulminant hepatitis B is associated with distinct mutational patterns of HBV, underlining that genomic diversity of the virus is an important factor determining its pathogenicity.
Keywords: Hepatitis B Virus; Liver Failure, Acute; Human Genome Project
Thomas Mina, Samad Amini-Bavil-Olyaee, Frank Tacke, Piet Maes, Marc Van Ranst, Mahmoud Reza Pourkarim
3. Epidemiological history and genomic characterization of non-D1 HBV strains identified in Iran
Background: Hepatitis B virus (HBV) has been classified into eight genotypes and forty subgenotypes. Genotype D of HBV is the most worldwide distributed genotype and HBV subgenotype D1 has been isolated from Iranian patients.
Objective: To characterize for the first time complete genomes of recently emerged non-D1 strains in Iran.
Study design: HBV complete genomes isolated from 9 Iranian HBV carriers were sequenced. Different diversities of the ORFs were mapped and evolutionary history relationships were investigated.
Results: Phylogenetic analysis identified four D2 subgenotypes and five D3 subgenotypes of HBV in the studied patients. Of note, D2 strains clustered with strains from Lebanon and Syria. The time of the most recent common ancestor (TMRCA) of the first cluster of D2 was dated at 1953 (BCI = 1926, 1976) while the second cluster was dated at 1947 (BCI = 1911, 1978). All five Iranian D3 strains formed a monophyletic cluster with Indian strain and dated back to 1967 (BCI = 1946, 1987). Surprisingly, two D3 strains had an adw2 subtype. Interestingly, more than 80% of the present strains showed precore mutations, while two isolates carried basal core promoter variation.
Conclusion: Iranian D2 and D3 isolates were introduced on at least two and one occasion in Iran and diverged from west and south Asian HBV strains, respectively. Considering the impact of the different (sub) genotypes on clinical outcome, exploring the distinct mutational patterns of Iranian D1 and non-D1 strains is of clinical importance.
Andrea-Clemencia Pineda-Peña, Nuno Rodrigues Faria, Thomas Mina, Samad Amini-Bavil-Olyaee, Seyed Moayed Alavian, Philippe Lemey, Piet Maes, Marc Van Ranst, Mahmoud Reza Pourkarim
4. 15 year fulminant hepatitis B follow-up in Belgium: Viral evolution and signature of demographic change
Abstract: Fulminant hepatitis among different clinical outcomes of hepatitis B virus infection is very rare and manifests high mortality rate, however it has not been investigated in Belgian inhabitants yet. In the frame of a retrospective study between 1995 and 2010, 80 serum samples (in some cases serial samples) archived in Biobank, were collected from 24 patients who had clinically developed fulminant infection of hepatitis B virus. In total, 33 hepatitis B virus (HBV) strains (31 full-length genome and 2 partial viral genes) of different HBV genotypes and subgenotypes including A2, B2, D1, D2, D3 and E, were amplified, sequenced and phylogenetically analyzed. HBV isolated strains from native and exotic patients were characterized by genome variations associated with viral invasiveness. Although several mutations at nucleotide and protein levels were detected, evolutionary analyses revealed a negative selective pressure over the viral genomes. This study revealed influence of immigration through a steady change in the viral epidemiological profile of the Belgian population.
Thomas Mina, Samad Amini-Bavil-Olyaee, Elham Shivrani-Dastgerdi, Nidia Sequeira Trovao, Marc Van Ranst, Mahmoud Reza Pourkarim
6. Reconstruction of the origin and dispersal of the worldwide dominant Hepatitis B Virus subgenotype D1
Abstract: Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus (HBV). HBV-D1 is the dominant subgenotype in the Mediterranean basin, Eastern Europe, and Asia. However, little is currently known about its evolutionary history and spatio-temporal dynamics. We use Bayesian phylodynamic inference to investigate the temporal history of HBV-D1, for which we calibrate the molecular clock using ancient sequences, and reconstruct the viral global spatial dynamics based, for the first time, on full-length publicly available HBV-D1 genomes from a wide range of sampling dates. We pinpoint the origin of HBV subgenotype D1 before the current era (BCE) in Turkey/Anatolia. The spatial reconstructions reveal global viral transmission with a high degree of mixing. By combining modern-day and ancient sequences, we ensure sufficient temporal signal in HBV-D1 data to enable Bayesian phylodynamic inference using a molecular clock for time calibration. Our results shed light on the worldwide HBV-D1 epidemics and suggest that this originally Middle Eastern virus significantly affects more distant countries, such as those in mainland Europe.
Nídia Sequeira Trovão, Marijn Thijssen, Bram Vrancken, Andrea-Clemencia Pineda-Peña, Thomas Mina, Samad Amini-Bavil-Olyaee, Philippe Lemey, Guy Baele, Mahmoud Reza Pourkarim.