Mutation of nucleotide 1,762 in the core promoter region during hepatitis B e seroconversion and its relation to liver damage in hepatitis B e antigen carriers.
In chronic hepatitis B virus (HBV) infection, mutations develop frequently at nucleotides 1,762/1,764 in the X protein open reading frame, where the core promoter is also located. By using a modified allele-specific polymerase chain reaction method, the longitudinal emergence of the A-->T mutation at nucleotide 1,762 was studied in relation to precore mutations, genotype, and liver damage. First, samples from 38 carriers that were drawn before and after hepatitis B e (HBe) seroconversion were tested. T-1,762 mutant strains increased during HBe seroconversion (P = 0.004). In the HBe antigen-negative (HBeAg-) phase, T-1,762 mutants were found in 71% (12 of 17) of patients without compared with 33% (6 of 18) of patients with a concomitant precore mutation that prevents HBeAg synthesis (P = 0.08). Second, in 55 HBeAg+ patients, the T-1,762 mutant was found to be associated with more liver inflammation (P = 0.04) and fibrosis (P = 0.02), as measured by histology activity index (HAI) scores. The results show that the nucleotide (nt) 1,762 A-->T mutation often develops during HBe seroconversion, particularly in strains without precore mutations that prevent HBeAg production. For unknown reasons, the T-1,762 mutant was rare in genotype B strains. The presence of a T-1,762 mutant in the HBeAg+ phase may be useful for identifying immunoactivation in previously immunotolerant carriers, which could be valuable for selecting patients for interferon therapy.
Lindh
M
M
Department of Clinical Virology, Göteborg University, Sweden. magnus.lindh@microbio.gu.se
Gustavson
C
C
Mårdberg
K
K
Norkrans
G
G
Dhillon
A P
AP
Horal
P
P
D002353:Carrier State / Q000821:virology; D004252:DNA Mutational Analysis; D005838:Genotype; D006509:Hepatitis B / Q000473:pathology / Q000821:virology*; D006510:Hepatitis B Antibodies / Q000097:blood; D006512:Hepatitis B Core Antigens / Q000235:genetics*; D006513:Hepatitis B e Antigens / Q000097:blood*; D006515:Hepatitis B virus / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008099:Liver / Q000473:pathology*; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic
D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D006513:Hepatitis B e Antigens