Hepatitis B virus (HBV) is an oncogenic virus. An estimated 400 million individuals worldwide are infected with HBV leading to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The early events of HBV infection are poorly defined due to the low signal intensity, transient and dynamic nature of the entry process, and lack of a systemic approach to identify the cellular components required for individual steps. Once characterized, these host factors may serve as critical targets for therapeutic intervention, thus reducing the rate of chronic hepatitis and ensuing liver cancer. Duck hepatitis B virus (DHBV), the related hepatotropic DNA virus may serve as a model system for the identification of viral receptor/co-factors as well as for the evaluation of novel molecular targets for intervention of hepadnavirus infection. We have previously identified and cloned two DHBV pre-S envelope-interacting proteins: p170 (carboxypeptidase D, DCPD) and p120 (glycine decarboxylase). The DCPD has been established as a DHBV docking receptor but fails to confer DHBV susceptibility of cell lines, suggesting that other cellular co-factors are necessary for establishing productive viral infection. The p120 is distributed only in DHBV infectible tissues and essential for a post-binding step of the DHBV life cycle. Optimal p120 binding in vitro requires truncation of the pre-S domain, which contains a putative cleavage site for PC7, a proprotein convertase. Our long-term goal is to understand virus-host interactions in the viral entry pathway and identify cellular targets for therapeutic intervention. The present application will initiate investigations on the mode of p120 action.
Our specific aims are: (1). Investigate the molecular basis whereby p120 mediates productive DHBV infection; (2). Determine the contribution of proprotein convertases to DHBV infectivity; and (3). Evaluate p120 as well as DCPD as molecular targets for intervention of DHBV infection. We hope these studies will contribute to the understanding of the early events of hepadnavirus infection and may lead to the development of novel antiviral strategies for prevention of HBV induced liver cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109733-02
Application #
7054040
Study Section
Virology - A Study Section (VIRA)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2005-04-15
Project End
2010-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$220,445
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
Qin, Yanli; Tang, Xiaoli; Garcia, Tamako et al. (2011) Hepatitis B virus genotype C isolates with wild-type core promoter sequence replicate less efficiently than genotype B isolates but possess higher virion secretion capacity. J Virol 85:10167-77
Gutelius, Danielle; Li, Jisu; Wands, Jack et al. (2011) Characterization of the pleiotropic effects of the genotype G-specific 36-nucleotide insertion in the context of other hepatitis B virus genotypes. J Virol 85:13278-89
(2011) Corrigendum to: Hepatitis C virus NS2 protein triggers endoplasmic reticulum stress and suppresses its own viral replication [J Hepatol. 2010 Nov;53(5):797–804] J Hepatol 55:239
Qin, Yanli; Zhang, Jiming; Garcia, Tamako et al. (2011) Improved method for rapid and efficient determination of genome replication and protein expression of clinical hepatitis B virus isolates. J Clin Microbiol 49:1226-33
von dem Bussche, Annette; Machida, Raiki; Li, Ke et al. (2010) Hepatitis C virus NS2 protein triggers endoplasmic reticulum stress and suppresses its own viral replication. J Hepatol 53:797-804
Ito, Kiyoaki; Qin, Yanli; Guarnieri, Michael et al. (2010) Impairment of hepatitis B virus virion secretion by single-amino-acid substitutions in the small envelope protein and rescue by a novel glycosylation site. J Virol 84:12850-61
Tong, Yupin; Tong, Shuping; Zhao, Xiaoai et al. (2010) Initiation of duck hepatitis B virus infection requires cleavage by a furin-like protease. J Virol 84:4569-78
Tsai, Adrienne; Kawai, Shigenobu; Kwei, Karen et al. (2009) Chimeric constructs between two hepatitis B virus genomes confirm transcriptional impact of core promoter mutations and reveal multiple effects of core gene mutations. Virology 387:364-72
Garcia, Tamako; Li, Jisu; Sureau, Camille et al. (2009) Drastic reduction in the production of subviral particles does not impair hepatitis B virus virion secretion. J Virol 83:11152-65
Kim, Eun; Li, Ke; Lieu, Charmiane et al. (2008) Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and correlates with liver steatosis. J Hepatol 49:787-98

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