title: Naturally occurring deletions/insertions in HBV core promoter tend to decrease in hepatitis B e antigen-positive chronic hepatitis B patients during antiviral therapy.
abstract: BACKGROUND
  Mutations in HBV core promoter (CP) are suggested to affect viral replication and disease progression. We investigated CP deletion/insertion mutations (Del/Ins) in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients before and during antiviral treatment.
  
  
  METHODS
  Direct and clone sequencings were used for detection of CP Del/Ins in 12 patients. The dynamic changes of CP Del/Ins were tracked in these cases until week 48 of treatment. The effects of Del/Ins on CP activities and hepatitis B X protein (HBx) were analysed using luciferase assay and sequence comparison, respectively. Furthermore, 292 untreated HBeAg-positive CHB cases were also analysed.
  
  
  RESULTS
  Twelve cases with multi-peak PCR direct sequencing electropherograms at baseline were confirmed to have CP Del/Ins by clone sequencing, with detection rates varying from 14.8% to 93.3% of clones analysed. Follow-up studies showed the detection rates of CP Del/Ins in patients decreased from 100% (12/12) at baseline to 16.7% (2/12) at week 48 of treatment (P<0.001), in parallel with a decline in HBV DNA, hepatitis B surface antigen (HBsAg), alanine aminotransferase (ALT) and aspartate transaminase (AST) levels along with an increase in HBeAg loss. Luciferase assay results showed distinct promoter activities among Del/Ins-harbouring CP sequences. Importantly, 71.8% (148/206) of Del/Ins sequences potentially resulted in HBx carboxy-terminal truncations. CP Del/Ins mutations were also found in 27.4% (80/292) of untreated cases.
  
  
  CONCLUSIONS
  Naturally occurring complex of CP Del/Ins mutants existed in untreated HBeAg-positive CHB patients. These mutations would affect HBV transcription activities and integrity of HBx, which might correlate with disease progression. Their prevalence decreases on antiviral therapy in parallel with the decline in HBV DNA, HBsAg and ALT and AST levels.
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Peng
authors.forename: Baoming
authors.initials: B
authors.lastname: Liu
authors.forename: Jinlin
authors.initials: J
authors.lastname: Hou
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.forename: Ran
authors.initials: R
authors.lastname: Hao
authors.forename: Kuanhui
authors.initials: K
authors.lastname: Xiang
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhuang
authors.forename: Tong
authors.initials: T
authors.lastname: Li
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000097:blood; D001483:Base Sequence; D002999:Clone Cells; D004279:DNA, Viral / Q000037:antagonists & inhibitors / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter; D006512:Hepatitis B Core Antigens / Q000235:genetics* / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000235:genetics* / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D054643:INDEL Mutation; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D008156:Luciferases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase