title: In Vitro Studies Show that Sequence Variability Contributes to Marked Variation in Hepatitis B Virus Replication, Protein Expression, and Function Observed across Genotypes.
abstract: The hepatitis B virus (HBV) exists as 9 major genotypes (A to I), one minor strain (designated J) and multiple subtypes. Marked differences in HBV natural history, disease progression and treatment response are exhibited by many of these genotypes and subtypes. For example, HBV genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion and high rates of liver cancer compared to other HBV genotypes, whereas genotype A2 is rarely associated with HBeAg-negative disease or liver cancer. The reasons for these and other differences in HBV natural history are yet to be determined but could in part be due to sequence differences in the HBV genome that alter replicative capacity and/or gene expression. Direct comparative studies on HBV replication and protein expression have been limited to date due largely to the absence of infectious HBV cDNA clones for each of the HBV genotypes present in the same genetic arrangement. We have produced replication-competent infectious cDNA clones of the most common subtypes of genotypes A to D, namely, A2, B2, C2, D3, and the minor strain J, and compared their HBV replication phenotype using transient-transfection models. We identified striking differences in HBV replicative capacity as well as HBeAg and surface (HBsAg) protein expression across genotypes, which may in part be due to sequence variability in regulatory regions of the HBV genome. Functional analysis showed that sequence differences in the major upstream regulatory region across genotypes impacted promoter activity.
  
  
  OBJECTIVE
  There have been very few studies directly comparing the replication phenotype of different HBV genotypes, for which there are marked differences in natural history and disease progression worldwide. We have generated replication-competent 1.3-mer cDNA clones of the major genotypes A2, B2, C2, and D3, as well as a recently identified strain J, and identified striking differences in replicative capacity and protein expression that may contribute to some of the observed differences in HBV natural history observed globally.
authors: Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital Peter Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia.
authors: Vitina
authors: V
authors: Sozzi
authors: Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital Peter Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia.
authors: Renae
authors: R
authors: Walsh
authors: Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital Peter Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia.
authors: Margaret
authors: M
authors: Littlejohn
authors: Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital Peter Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia.
authors: Danni
authors: D
authors: Colledge
authors: Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital Peter Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia.
authors: Kathy
authors: K
authors: Jackson
authors: Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital Peter Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia.
authors: Nadia
authors: N
authors: Warner
authors: Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital Peter Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia.
authors: Lilly
authors: L
authors: Yuen
authors: Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital Peter Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia.
authors: Stephen A
authors: SA
authors: Locarnini
authors: Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital Peter Doherty Institute of Infection and Immunity, Melbourne, Victoria, Australia peter.revill@mh.org.au.|University of Melbourne, Department of Microbiology and Immunology, Melbourne, Victoria, Australia.
authors: Peter A
authors: PA
authors: Revill
mesh_terms: D045744:Cell Line, Tumor; D004261:DNA Replication / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006513:Hepatitis B e Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000821:virology; D010641:Phenotype; D019562:Viral Load / Q000235:genetics; D014779:Virus Replication / Q000235:genetics*
chemical_list: D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens