title: Impact of hepatitis B virus (HBV) preS/S genomic variability on HBV surface antigen and HBV DNA serum levels.
abstract: To evaluate whether hepatitis B virus (HBV) preS/S gene variability has any impact on serum hepatitis B surface antigen (HBsAg) levels and to analyze the replication capacity of naturally occurring preS/S variants, sera from 40 untreated patients with HBV-related chronic liver disease (hepatitis B e antigen [HBeAg]-positive, n = 11; HBeAg-negative, n = 29) were virologically characterized. Additionally, phenotypic analysis of three different preS/S variant isolates (carrying a 183-nucleotide deletion within the preS1 region, the deletion of preS2 start codon, and a stop signal at codon 182 within the S gene, respectively) was performed. HBV infecting 14 (35%) patients had single or multiple preS/S genomic mutations (i.e., preS1 and/or preS2 deletions, preS2 start codon mutations, C-terminally truncated and/or "a" determinant mutated S protein). Presence of preS/S variants negatively correlated with HBsAg titers (r = -0.431; P = 0.005) and its prevalence did not significantly differ between HBeAg-positive and HBeAg-negative patients. No correlation was found between HBsAg and HBV DNA levels in patients infected with preS/S mutants, whereas a significant correlation was found between HBsAg and viremia levels (r = 0.607; P = 0.001) in patients infected with wild-type HBV strains. HepG2 cells replicating the above-mentioned three preS/S variants showed significant reduction of HBsAg secretion, retention of envelope proteins in the endoplasmic reticulum, less efficient virion secretion and nuclear accumulation of significantly higher amounts of covalently closed circular DNA compared with wild-type HBV replicating cells.
  
  
  CONCLUSIONS
  In patients infected with preS/S variants, HBV DNA replication and HBsAg synthesis/secretion appear to be dissociated. Therefore, the use of HBsAg titer as diagnostic/prognostic tool has to take into account the frequent emergence of preS/S variants in chronic HBV infection.
authors.affiliation: Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University of Messina, Messina, Italy. tpollicino@unime.it
authors.forename: Teresa
authors.initials: T
authors.lastname: Pollicino
authors.forename: Giuliana
authors.initials: G
authors.lastname: Amaddeo
authors.forename: Agnese
authors.initials: A
authors.lastname: Restuccia
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Raffa
authors.forename: Angela
authors.initials: A
authors.lastname: Alibrandi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Cutroneo
authors.forename: Angelo
authors.initials: A
authors.lastname: Favaloro
authors.forename: Sergio
authors.initials: S
authors.lastname: Maimone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Squadrito
authors.forename: Giovanni
authors.initials: G
authors.lastname: Raimondo
mesh_terms: D000328:Adult; D004279:DNA, Viral / Q000097:blood; D004721:Endoplasmic Reticulum / Q000821:virology; D005260:Female; D014644:Genetic Variation; D016679:Genome, Viral / Q000235:genetics* / Q000276:immunology; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics* / Q000254:growth & development / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000276:immunology* / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D014766:Viremia / Q000097:blood / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000235:genetics
chemical_list: D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D014759:Viral Envelope Proteins