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Hepatitis B virus (HBV) infection is a global health problem, and more than 350 million people in the world are chronic carriers of the virus.1 The clinical manifestations of HBV infection range from acute self-limiting infection or fulminant hepatic failure, inactive carrier state, chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma (HCC).2 Pathogenesis of HBV infection is usually through the interaction between virus and host immune responses to HBV-encoded antigens.3 In the natural course of chronic HBV infection, early seroconversion from hepatitis B e-antigen (HBeAg) to anti-HBe (immune clearance phase) usually indicates a favorable outcome, because it is usually accompanied by the cessation of HBV replication and non-progressive liver disease.2,4 In contrast, late seroconversion of HBeAg after multiple bouts of reactivation and remission may accelerate the progression of chronic hepatitis B and thus have a poor clinical outcome.5,6

Having only 3200 base pairs in its genome, HBV is the smallest known DNA virus.1 The partially double-stranded circular HBV-DNA consists of four overlapping genes encoding the viral envelope (pre-S and S), nucleocapsid (precore and core), polymerase with error-prone reverse transcriptase activity, and X-protein. Because of the spontaneous error rate of viral reverse transcriptase, the HBV genome evolves with an estimated rate of nucleotide substitution at 1.4–3.2 × 10–5/site per year.7 After a long-time evolution, currently four major HBV subtypes (adw, ayw, adr and ayr) are identified by the antigenic determinants of surface antigen (HBsAg) and seven HBV genotypes (A to G) are defined by divergence in the entire HBV genomic sequence > 8%.8–10 The interrelation of subtypes to genotypes has been clarified,8,9 genomes encoding adw are found in genotypes A–C, F, and G, while the genomes encoding both adr and ayr occur in genotype C alongside with adw. Most of the HBV subtypes or genotypes have distinct geographic distributions.8,9

Similarly, genotypic classification of other hepatotropic viruses such as hepatitis C virus (HCV) and hepatitis D virus (HDV) is also well documented.11,12 However, the relationship between HCV or HDV genotypes and severity of liver disease remains controversial. HCV genotype 1b and HDV genotype I have been reported to be more pathogenic than other genotypes.12,13 By contrast, the influence of HCV genotypes on the response to treatment with interferon alone or in combination with ribavirin is clearly established; sustained response to antiviral therapy is significantly lower in patients with HCV genotype 1 infection.14 Although serological and genotypic classifications of HBV have been confirmed, the clinical relevance of HBV subtypes or genotypes in terms of clinical outcomes and therapeutic response to antiviral therapy in patients with chronic HBV infection is infrequently mentioned, until very recently. Several studies, most from Taiwan and Japan, have shown that HBV genotype C is associated with the development of HCC,15–17 and has a lower response rate to interferon therapy as compared to genotype B.18 Whether these interesting observations hold true in other parts of the world, particularly the countries where HBV genotypes A and D prevail, awaits further studies.

In this issue of the Journal, Thakur et al.19 prospectively studied the prevalence and clinical significance of HBV genotypes in 130 histologically proven chronic HBV infected Indian patients. Their results showed that HBV genotypes A and D were prevalent in Indian patients with HBV-related chronic liver disease; however, genotype D was more common in incidentally detected asymptomatic HBsAg-positive subjects (IDAHS) with hepatic arterial infusion score > 4 and in patients with higher Child’s scores compared to genotype A. In addition, the prevalence of genotype D tended to be higher in HCC patients younger than 40 years of age than that in age-matched IDAHS. They therefore concluded that HBV genotype D was associated with more severe liver disease and may predict occurrence of HCC in young patients. Their findings indeed provided additional evidence to support the speculation of possible pathogenic differences among HBV genotypes but warrant further analysis in large-scale longitudinal studies to clarify the natural history of patients infected with different HBV genotypes. Moreover, the molecular virological mechanisms that contribute to these clinical differences among HBV genotypes remain to be explored.

Several HBV variants have been found to display alteration of epitopes important in the host immune recognition, enhanced virulence with increased replication of HBV, resistance to antiviral therapies or facilitated cell attachment/penetration.20 Among these variants, isolates with an adenine (A) to thymine (T) transversion at nucleotide 1762 together with a guanine (G) to adenine (A) transition at nucleotide 1764 (T1762/A1764) mutations in the basal core promoter (nucleotides 1742–1849) are often present in hepatitis B carriers with chronic hepatitis, fulminant hepatitis and HCC, and less often in inactive carriers and immunosuppressed patients.21 Previous studies have indicated that HBV genotype C has a higher frequency of T1762/A1764 mutation as compared to genotype B.18,22 Furthermore, a higher frequency of basal core promoter mutant has been found in HCC patients than asymptomatic carriers (66–90% compared with 11–47%),23,24 and the frequency of this mutant has been reported to increase with progression of liver disease.25 It is proposed that changes in the secondary structure of pregenome, given rise to by T1762/A1764 mutation, may increase viral replication through the enhancement of core protein synthesis and creation of a binding site for hepatocyte nuclear factor (HNF1) transcription factor.26 On the other hand, the X-gene of HBV genome encodes two proteins that have potent transactivation activities on viral as well as cellular genes.27 This property makes the X-gene a candidate for a role in the development of HCC in patients with chronic HBV infection. Since its coding sequence overlaps regions of crucial importance for virus replication such as enhancer II and core promoter, mutations in this region may therefore induce not only an amino acid change in the X-protein but also an alteration of HBV gene expression.20,28 For example, T1762/A1764 mutations in the basal core promoter are non-synonymous that may affect the structure of the X-protein. These mutations convert amino acids 130 and 131 of the overlapping X-coding region from lysine to methionine and valine to isoleucine, respectively. The amino acid changes caused by these mutations in the presence of serine/serine caused by changes at nucleotides 1809/1812 could therefore alter the structure of the X-protein and thus contribute to hepatocarcinogenesis.24 Taken together, the basal core promoter mutation may serve as a candidate molecular marker to account for the pathogenic differences among HBV genotypes. However, further studies are awaited to prove or disprove this speculation.

It is well known that the host–viral interaction plays a pivotal role in the pathogenesis of HBV infection.3 With the recent advances in genomic and immunological technologies, future research focused on the interplay between molecular virological factors and host factors will shed much light on the understanding of pathogenic differences among different HBV genotypes.


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