title: Stronger enhancer II/core promoter activities of hepatitis B virus isolates of B2 subgenotype than those of C2 subgenotype.
abstract: Hepatitis B virus (HBV) genotype C causes prolonged chronic infection and increased risk for liver cancer than genotype B. Our previous work revealed lower replication capacity of wild-type genotype C2 than B2 isolates. HBV DNA replication is driven by pregenomic RNA, which is controlled by core promoter (CP) and further augmented by enhancer I (ENI) and enhancer II (ENII). DNA fragments covering these regulatory elements were amplified from B2 and C2 isolates to generate luciferase reporter constructs. As ENII is fully embedded in CP, we inserted HBV DNA fragments in the sense orientation to determine their combined activities, and in the antisense orientation to measure enhancer activities alone. Genotype B2 isolates displayed higher ENI+ENII+CP, ENII+CP, and ENII activities, but not ENI or ENI+ENII activity, than C2 isolates. The higher ENII+CP activity was partly attributable to 4 positions displaying genotype-specific variability. Exchanging CP region was sufficient to revert the replication phenotypes of several B2 and C2 clones tested. These results suggest that a weaker ENII and/or CP at least partly accounts for the lower replication capacities of wild-type C2 isolates, which could drive the subsequent acquisition of CP mutations. Such mutations increase genome replication and are implicated in liver cancer development.
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Infectious Diseases, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Xueshi
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Haodi
authors.initials: H
authors.lastname: Jia
authors.affiliation: Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jiming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|The Liver Research Center, Rhode Island Hospital, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
authors.forename: Shuping
authors.initials: S
authors.lastname: Tong
mesh_terms: D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D014644:Genetic Variation; D005838:Genotype; D006515:Hepatitis B virus / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D014779:Virus Replication