Chronic infection with hepatitis B virus (HBV) greatly increases the risk to develop hepatocellular carcinoma (HCC), and genotypes B and C account for majority of chronic HBV infection worldwide. Although these two genotypes infect similar human population (Asians) via the same (vertical) mode of transmission, infection with genotype C is associated with prolonged active virus replication, delayed HBeAg seroconversion, and increased lifelong risk for HCC. Genotype C is also more prone to develop core promoter mutations, which have been independently associated with HCC risk. Our preliminary studies revealed that core promoter mutations up regulate genome replication and core protein expression when introduced into clones of genotype A and C. We also found that most genotype C isolates with wild-type core promoter sequence produce less pregenomic RNA than corresponding genotype B isolates, leading to lower core protein expression and genome replication. Nevertheless, they are more efficient at virion secretion. Considering that the core protein is a strong immunogen, we hypothesize that its low expression by genotype C prolongs the immune tolerance phase of infection and delays HBeAg seroconversion, whereas efficient virion secretion ensures rapid virus spread in the liver as required for establishment of persisten infection. We also hypothesize that immune clearance mechanisms select for genotype C mutants with augmented replication capacity through core promoter mutations, with the concomitant increase in core protein expression triggering liver damage and HCC risk. In this R21 grant application we will identify the determinants and elucidate the mechanisms responsible for lower genome replication capacity of wild-type genotype C isolates but more efficient virion secretion. We will also test the alternative possibility that the low prevalence o core promoter mutations in genotype B is due to their inability to enhance genome replication in this particular genotype. Our working hypothesis and proposed studies will shed light on the higher prevalence of core promoter mutations in genotype C, and help solve the longstanding puzzle of why genotype C persists longer in the host to induce advanced liver diseases such as cirrhosis and HCC. These studies will also reveal novel control mechanisms in HBV genome replication and virion secretion. Our rich experience and proven track record in characterizing biological properties of HBV genetic variants will ensure successful completion of the proposed study.

Public Health Relevance

Hepatitis B virus chronically infects at least 300 million people worldwide, and these people are much more likely to develop liver cancer than noninfected individuals. This study will focus on the two strains of hepatitis B virus responsible for most of chronic infection and liver cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI103648-01
Application #
8428335
Study Section
Virology - B Study Section (VIRB)
Program Officer
Koshy, Rajen
Project Start
2013-01-15
Project End
2014-12-31
Budget Start
2013-01-15
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$198,750
Indirect Cost
$73,750
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
Zong, Li; Qin, Yanli; Jia, Haodi et al. (2017) Differential regulation of hepatitis B virus core protein expression and genome replication by a small upstream open reading frame and naturally occurring mutations in the precore region. Virology 505:155-161
Qin, Yanli; Wang, Yong-Xiang; Zhang, Jiming et al. (2017) Generation of Replication-Competent Hepatitis B Virus Genome from Blood Samples for Functional Characterization. Methods Mol Biol 1540:219-226
Zhou, Huailiang; Gewaily, Dina; Ahn, Sang Hoon et al. (2017) Sequence analysis and functional characterization of full-length hepatitis B virus genomes from Korean cirrhotic patients with or without liver cancer. Virus Res 235:86-95
Zhang, Fei; Tang, Xiaoli; Garcia, Tamako et al. (2017) Characterization of contrasting features between hepatitis B virus genotype A and genotype D in small envelope protein expression and surface antigen secretion. Virology 503:52-61
Chen, Chaoyang; Jia, Haodi; Zhang, Fei et al. (2016) Functional characterization of hepatitis B virus core promoter mutants revealed transcriptional interference among co-terminal viral mRNAs. J Gen Virol 97:2668-2676
Li, Jisu; Zong, Li; Sureau, Camille et al. (2016) Unusual Features of Sodium Taurocholate Cotransporting Polypeptide as a Hepatitis B Virus Receptor. J Virol 90:8302-13
Qin, Yanli; Zhou, Xueshi; Jia, Haodi et al. (2016) Stronger enhancer II/core promoter activities of hepatitis B virus isolates of B2 subgenotype than those of C2 subgenotype. Sci Rep 6:30374
Tong, Shuping; Revill, Peter (2016) Overview of hepatitis B viral replication and genetic variability. J Hepatol 64:S4-S16
Zong, Li; Qin, Yanli; Jia, Haodi et al. (2016) Two-way molecular ligation for efficient conversion of monomeric hepatitis B virus DNA constructs into tandem dimers. J Virol Methods 233:46-50
Li, Jisu; Tong, Shuping (2015) From DCPD to NTCP: the long journey towards identifying a functional hepatitis B virus receptor. Clin Mol Hepatol 21:193-9

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