Mechanism of HBV genome variability and replication of HBV mutants.
Naturally occurring mutations in the H13V genome have been extensively documented, yet the biological consequences of even the dominant mutations have not been well characterized. In a recent study of HBeAg-positive French patients infected with genotype A, we obtained full-length clones with high or low replication capacities in the transfected human hepatoma cells. Surprisingly, high replicating clones were all derived from low viremia samples, and harbored core promoter mutations. The highest replicating clones all contained point mutations in addition to those at 1762/1764, and site-directed mutagenesis confirmed their role in further enhancing genome replication and suppressing HBeAg expression. Several core promoter mutants were defective in virion secretion, and mapping experiments revealed three missense mutations in the small envelope protein to be responsible: I110M, G119E, and R169P The effect of I110M and G119E mutations can be relieved by another point mutation that creates a novel N-linked glycosylation site. Finally, the African/Asian subgroup of genotype A (genotype Aa) contains unique mutations and is associated with low viremia titers as well as low HBeAg prevalence. We found point mutations upstream of the precore ATG codon of genotype Aa suppressed HBeAg expression, while the G1862T mutation in the precore region greatly impaired viral replication. Thus, molecular characterization can shed light on viral properties associated with clinical infection.
Tong
Shuping
S
The Liver Research Center, Rhode Island Hospital, Brown Medical School, Providence, RI, USA. shuping_tong_md@brown.edu
D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D006509:Hepatitis B / Q000821:virology; D006512:Hepatitis B Core Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics* / Q000502:physiology; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014779:Virus Replication
D006512:Hepatitis B Core Antigens