Summary Hepatitis delta virus (HDV) is an RNA virus which leads to both acute and chronic forms of hepatitis. At present, HDV isolates have been classified into eight major genotypes distributed over different geographical regions. Recent increase in HDV sequences in Europe and worldwide has enabled us to revisit the taxonomic classification of HDV. A total of 116 large hepatitis delta antigen (L‐HDAg) nucleotide sequences and 13 full‐length HDV genome sequences belonging to genotype‐1 from our European cohort, as well as 621 L‐HDAg nucleotide sequences belonging to genotype‐1 to genotype‐8 retrieved from the GenBank NCBI were included in this study. All 116 isolates of our cohort and 341 of 621 isolates (60%) account for genotype‐1, while the remaining 40% of isolates were unevenly distributed across genotype‐2 to genotype‐8. Phylogenetic analysis of 98 L‐HDAg sequences selected after elimination of redundant sequences of all 737 isolates was performed to identify plausible subtypes within HDV genotype‐1. Pairwise genetic distances for L‐HDAg sequences were calculated to estimate the inter‐genotype and inter‐subtype differences. The HDV genotype‐1 isolates phylogenetically formed five distinct clusters (genotype 1a‐1e), each of them corresponding to a distinct geographic region. Two distinct subtypes for HDV genotype‐2 and ‐4 (ie ‐2a and ‐2b; ‐4a and ‐4b, respectively) could be identified based on isolate sequences from GenBank. The previously defined genotype‐1 to genotype‐8 have an inter‐genotypic difference of ≥10%, while the newly defined subtypes of genotype‐1, ‐2 and ‐4 show an inter‐subtype difference of ≥3% to <10% from the average diversity. In addition, we identified unique amino acid residues, known as specificity‐determining positions, amongst the proposed subtypes.
Hepatitis D virus (HDV) causes the most severe form of viral hepatitis, which may rapidly progress to liver cirrhosis and hepatocellular carcinoma (HCC). It has been estimated that 15–20 million people worldwide are suffering from the chronic HDV infection. Currently, no effective therapies are available to treat acute or chronic HDV infection. The remarkable sequence variability of the HDV genome, particularly within the hypervariable region has resulted in the provisional classification of eight major genotypes and various subtypes. We have developed a specialized database, HDVdb, which contains a collection of partial and complete HDV genomic sequences obtained from the GenBank and from our own patient cohort. HDVdb enables the researchers to investigate the genetic variability of all available HDV sequences, correlation of genotypes to epidemiology and pathogenesis. Additionally, it will contribute in understanding the drug resistant mutations and develop effective vaccines against HDV infection. The database can be accessed through a web interface that allows for static and dynamic queries and offers integrated generic and specialized sequence analysis tools, such as annotation, genotyping, primer prediction, and phylogenetic analyses.
Chronic HBV infection results in various clinical manifestations due to different levels of immune response. In recent years, hepatitis B treatment has improved by longterm administration of nucleos(t)ide analogues (NUCs) and peg-interferon. Nucleic acid polymers (NAPs; REP 2139-Ca and REP 2139-Mg) are new antiviral drugs that block the assembly of subviral particles, thus preventing the release of HBsAg and allowing its clearance and restoration of functional control of infection when combined with various immunotherapies. In the REP 102 study (NCT02646189), 9 of 12 patients showed substantial reduction of HBsAg and seroconversion to anti-HBs in response to REP 2139-Ca, whereas 3 of 12 patients did not show responses (>1 log reduction of HBsAg and HBV DNA from baseline). We characterized the dynamic changes of HBV quasispecies (QS) within the major hydrophilic region (MHR) of the 'pre-S/S' open reading frame including the 'a' determinant in responders and nonresponders of the REP 102 study and four untreated matched controls. HBV QS complexity at baseline varied slightly between responders and nonresponders (P = .28). However, these responders showed significant decline in viral complexity (P = .001) as REP 2139-Ca therapy progressed but no significant change in complexity was observed among the nonresponders (P = .99). The MHR mutations were more frequently observed in responders than in nonresponders and matched controls. No mutations were observed in 'a' determinant of major QS population which may interfere with the detection of HBsAg by diagnostic assays. No specific mutations were found within the MHR which could explain patients' poor HBsAg response during REP 2139-Ca therapy. K E Y W O R D S hepatitis B surface antigen, major hydrophilic region, nucleic acid polymer, quasispecies | 1455 USMAN et Al
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