TY - JOUR
T1 - Defective hepatitis B virus DNA is not associated with disease status but is reduced by polymerase mutations associated with drug resistance
AU - Preiss, Scott
AU - Littlejohn, Margaret
AU - Angus, Peter
AU - Thompson, Alex JV
AU - Desmond, Paul
AU - Lewin, Sharon R
AU - Sasadeusz, Joe
AU - Matthews, Gail
AU - Dore, G J
AU - Shaw, Tim
AU - Sozzi, Vitini
AU - Yuen, Lilly
AU - Lau, George
AU - Ayres, Anna
AU - Thio, Chloe L
AU - Avihingsanon, Anchalee
AU - Ruxrungtham, Kiat
AU - Locarnini, Stephen
AU - Revill, Peter A
PY - 2008
Y1 - 2008
N2 - Defective hepatitis B virus DNA (dDNA) is reverse-transcribed from spliced hepatitis B virus (HBV) pregenomic messenger RNA (pgRNA) and has been identified in patients with chronic HBV (CH-B). The major 2.2-kb spliced pgRNA encodes a novel HBV gene product, the hepatitis B splice protein (HBSP) via a deletion and frame shift within the polymerase. Although spliced RNA and HBSP expression have been associated with increased HBV DNA levels and liver fibrosis, the role of dDNA in HBV-associated disease is largely undefined. Our aims were to (1) compare the relative proportions of dDNA ( dDNA) in a range of HBV-infected serum samples, including patients with human immunodeficiency virus (HIV)/HBV coinfection and HBV-monoinfected persons with differing severities of liver disease, and (2) determine the effect of mutations associated with drug resistance on defective DNA production. Defective DNA was detected in 90 of persons with CH-B. There was no significant difference in the relative abundance of dDNA between the monoinfected and HIV/HBV-coinfected groups. We also found no association between the dDNA and alanine aminotransferase, hepatitis B e antigen status, HBV DNA levels, fibrosis levels, compensated or decompensated liver cirrhosis, genotype, or drug treatment. However, the dDNA was significantly lower in individuals infected with lamivudine-resistant (LMV-R) HBV compared with wild-type HBV (P <0.0001), indicating that antiviral drug resistance alters the balance between defective and genomic length DNA in circulation. Experiments in vitro using HBV encoding LMV-R mutations confirmed these results. CONCLUSION: Our results identified no association between dDNA and parameters associated with disease status and suggested that the relative abundance of dDNA is largely dependent on the integrity of the HBV polymerase and is unrelated to the severity of liver disease.
AB - Defective hepatitis B virus DNA (dDNA) is reverse-transcribed from spliced hepatitis B virus (HBV) pregenomic messenger RNA (pgRNA) and has been identified in patients with chronic HBV (CH-B). The major 2.2-kb spliced pgRNA encodes a novel HBV gene product, the hepatitis B splice protein (HBSP) via a deletion and frame shift within the polymerase. Although spliced RNA and HBSP expression have been associated with increased HBV DNA levels and liver fibrosis, the role of dDNA in HBV-associated disease is largely undefined. Our aims were to (1) compare the relative proportions of dDNA ( dDNA) in a range of HBV-infected serum samples, including patients with human immunodeficiency virus (HIV)/HBV coinfection and HBV-monoinfected persons with differing severities of liver disease, and (2) determine the effect of mutations associated with drug resistance on defective DNA production. Defective DNA was detected in 90 of persons with CH-B. There was no significant difference in the relative abundance of dDNA between the monoinfected and HIV/HBV-coinfected groups. We also found no association between the dDNA and alanine aminotransferase, hepatitis B e antigen status, HBV DNA levels, fibrosis levels, compensated or decompensated liver cirrhosis, genotype, or drug treatment. However, the dDNA was significantly lower in individuals infected with lamivudine-resistant (LMV-R) HBV compared with wild-type HBV (P <0.0001), indicating that antiviral drug resistance alters the balance between defective and genomic length DNA in circulation. Experiments in vitro using HBV encoding LMV-R mutations confirmed these results. CONCLUSION: Our results identified no association between dDNA and parameters associated with disease status and suggested that the relative abundance of dDNA is largely dependent on the integrity of the HBV polymerase and is unrelated to the severity of liver disease.
UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18571815
M3 - Article
VL - 48
SP - 741
EP - 749
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 3
ER -