Abstract
Molecular mechanisms related to occult hepatitis B virus (HBV) infection, particularly those based on genotype C infection, have rarely been determined thus far in the ongoing efforts to determine infection mechanisms. Therefore, we aim to elucidate the mutation patterns in the surface open reading frame (S ORF) underlying occult infections of HBV genotype C in the present study. Nested PCRs were applied to 624 HBV surface antigen (HBsAg) negative Korean subjects. Cloning and sequencing of the S ORF gene was applied to 41 occult cases and 40 control chronic carriers. Forty-one (6.6%) of the 624 Korean adults with HBsAg-negative serostatus were found to be positive for DNA according to nested PCR tests. Mutation frequencies in the three regions labeled here as preS1, preS2, and S were significantly higher in the occult subjects compared to the carriers in all cases. A total of two types of deletions, preS1 deletions in the start codon and preS2 deletions as well as nine types of point mutations were significantly implicated in the occult infection cases. Mutations within the “a” determinant region in HBsAg were found more frequently in the occult subjects than in the carriers. Mutations leading to premature termination of S ORF were found in 16 occult subjects (39.0%) but only in one subject from among the carriers (2.5%). In conclusion, our data suggest that preS deletions, the premature termination of S ORF, and “a” determinant mutations are associated with occult infections of HBV genotype C among a HBsAg-negative population. The novel mutation patterns related to occult infection introduced in the present study can help to broaden our understanding of HBV occult infections.
Highlights
Despite the availability of an effective vaccine, more than 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and many develop serious liver diseases as a result, such as cirrhosis or hepatocellular carcinoma (HCC) [1,2]
Because genotype C is known to be responsible for the majority of HBV infections in HBV endemic areas such as China, Korea and other Asia-Pacific nations and given that it is reportedly more virulent than genotype B [4], monitoring of mutation types in genotype C by means of nested PCR, in cases associated with occult infections, should be imperative for the appropriate control of hepatitis B in this area
A specific mutation type in the HBV preS/S region in occult cases may cause an alteration of HBV surface antigen (HBsAg) antigenicity or the secretion capacity, which may lead to vaccine escape infections and the emergence of high virulence variants in a population
Summary
Despite the availability of an effective vaccine, more than 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and many develop serious liver diseases as a result, such as cirrhosis or hepatocellular carcinoma (HCC) [1,2]. Occult HBV infection can be defined as the long-lasting persistence of viral genomes of individuals negative for the HBsAg serology [10,11,12]. Recent progress in molecular-based technology, such as PCR-based methods, has led to the ability to prove HBV infection in HBsAgnegative individuals with or without circulating antibodies to HBsAg and/or the hepatitis B core antigen [13,14,15]. HBV occult infection is reportedly related closely to severe forms of liver disease such as cirrhosis and HCC [16,17]. In patients infected with the hepatitis C virus, HBV co-infection becomes more dangerous [13,18,19,20]
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