title: Alpha/beta interferon differentially modulates the clearance of cytoplasmic encapsidated replication intermediates and nuclear covalently closed circular hepatitis B virus (HBV) DNA from the livers of hepatocyte nuclear factor 1alpha-null HBV transgenic mice.
abstract: Treatment with alpha interferon is a standard therapy for patients with chronic hepatitis B virus (HBV) infections. This treatment can reduce virus load and ameliorate disease symptoms. However, in the majority of cases, alpha interferon therapy fails to resolve the chronic HBV infection. The reason alpha interferon therapy is inefficient at resolving chronic HBV infections is assumed to be because it fails to eliminate covalently closed circular (CCC) HBV DNA from the nuclei of infected hepatocytes. In an attempt to address this issue, the stability of HBV CCC DNA in response to alpha/beta interferon induction was examined in HNF1alpha-null HBV transgenic mice. Alpha/beta interferon induction by polyinosinic-polycytidylic acid [poly(I-C)] treatment efficiently eliminated encapsidated cytoplasmic HBV replication intermediates while only modestly reducing nuclear HBV CCC DNA. These observations indicate that nuclear HBV CCC DNA is more stable than cytoplasmic replication intermediates in response to alpha/beta interferon induction. Consequently it appears that for therapies to resolve chronic HBV infection efficiently, they will have to target the elimination of the most stable HBV replication intermediate, nuclear HBV CCC DNA.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Anderson
authors.forename: Krista E
authors.initials: KE
authors.lastname: Banks
authors.forename: Marco
authors.initials: M
authors.lastname: Pontoglio
authors.forename: Moshe
authors.initials: M
authors.lastname: Yaniv
authors.forename: Alan
authors.initials: A
authors.lastname: McLachlan
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004270:DNA, Circular / Q000096:biosynthesis*; D004279:DNA, Viral / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000628:therapy; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D022781:Hepatocytes / Q000378:metabolism*; D007369:Interferon Inducers / Q000494:pharmacology; D016898:Interferon-alpha / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D011070:Poly I-C / Q000494:pharmacology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics
chemical_list: D004270:DNA, Circular; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D007369:Interferon Inducers; D016898:Interferon-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D016899:Interferon-beta; D011070:Poly I-C