PreS and core gene heterogeneity in hepatitis B virus (HBV) genomes isolated from patients with long-lasting HBV chronic infection.

Several reports have been recently published concerning the identification of HBV variants due to rearrangements of the preS1/preS2 or core regions of the viral genome. To evaluate the frequency of the natural occurrence of such variants and whether the heterogeneity of these genomic regions correlates with the severity of the liver disease, we have examined the preS1/preS2 region and the entire core gene sequences of HBV DNA isolated from sera of 30 chronic HBV carriers, 7 with chronic persistent hepatitis, 10 with chronic active hepatitis, 7 with cirrhosis, and 6 with hepatocellular carcinoma. We found no significant rearrangement in any of the preS1 regions examined, while genomic modifications precluding the preS2 protein production were detected in 4 cases, 2 with cirrhosis and 2 with hepatocellular carcinoma. The analysis of the core gene showed the presence of various numbers of missense mutations in the core region of most cases, independent of the grade of liver disease. Moreover, in contrast with previous reports, neither mutation cluster region nor deletion was observed. On the contrary, HBV strains with the precore mutation at nucleotide position 1896, effecting the rise of HBeAg-defective viruses, were found in 26 of the 30 cases examined. In conclusion, our data show that the precore mutant is the only HBV genomic variant commonly selected during a chronic infection. Other HBV variants, due to genomic rearrangements outside the precore region, may exist and influence the outcome of the infection and the course of the liver disease, but the emergence of each of these variants seems to be an unusual and probably casual event.