Hepatitis B virus (HBV) infection is a significant health burden woddwide. Over 350 million individuals are chronically infected with HBV and ~600,000 deaths annually are attributed to HBV-related liver disease. It is the leading cause of hepatocellular carcinoma worldwide. Seven therapies for HBV are available in the clinic but none are a cure. A better understanding ofthe HBV life cycle on the molecular and cellular level will lead to new therapies for HBV. The capsid is an attractive target for therapy because of its central role in virus replication. Beyond its well-characterized role as a structural component ofthe virus, the capsid is a dynamic entity that plays roles in multiple processes such as genome replication, its intracellular trafficking, cccDNA synthesis, and virus morphogenesis. Project 2 seeks to establish new understandings ofthe mechanisms of these roles ofthe HBV capsid. This present proposal builds upon progress engendered during the current funding period. This project has four aims: 1) to understand how perturbation ofthe capsid dimer-dimer interface impacts the HBV life cycle;2) to visualize HBV assembly and replication using live cell imaging;3) to better understand the relationship between DNA maturation, capsid maturation and virion secretion using avian hepadnaviruses;and 4) to use hepatocyte-like cells derived from embryonic stem cells to study early events in HBV infection. These studies will uncover new understandings of mechanisms of virus replication and identify targets for new and better HBV therapies. Project 2 is dependent on productive interactions with Project 3 for knowledge and expertise on live cell imaging.
Aim 4 has the potential for important interactions with Project 5 in the use of mice with humanized immune systems to study HBV:host interactions. Current research findings from Project 2 have influenced new research directions in Project 1 with regard to ZASCI's role in cervical carcinogenesis. Project 2 relies heavily on all three cores, including all instruments supported by the Instrument Core, HBV production capabilities of the Virus Core, and statistical analysis of experimental design and results from the Admin./Stats Core.
Hepatitis B virus (HBV) is a worldwide health problem and causes liver diseases including cancer. Our research will lead to understandings of how HBV replicates and maintains an infection. For example, we are learning how HBV uses the liver cell to promote its own replication. Our research will uncover new mechanisms of HBV replication and identify targets for new and better HBV therapies.
|Park, Jung Wook; Nickel, Kwangok P; Torres, Alexandra D et al. (2014) Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage. Radiother Oncol 113:337-44|
|Wang, Lu; Zhao, Zibo; Meyer, Mark B et al. (2014) CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell 25:21-36|
|Kuzembayeva, Malika; Hayes, Mitchell; Sugden, Bill (2014) Multiple functions are mediated by the miRNAs of Epstein-Barr virus. Curr Opin Virol 7:61-5|
|Wang, Joseph Che-Yen; Nickens, David G; Lentz, Thomas B et al. (2014) Encapsidated hepatitis B virus reverse transcriptase is poised on an ordered RNA lattice. Proc Natl Acad Sci U S A 111:11329-34|
|Stein, Andrew P; Saha, Sandeep; Yu, Menggang et al. (2014) Prevalence of human papillomavirus in oropharyngeal squamous cell carcinoma in the United States across time. Chem Res Toxicol 27:462-9|
|Iempridee, Tawin; Reusch, Jessica A; Riching, Andrew et al. (2014) Epstein-Barr virus utilizes Ikaros in regulating its latent-lytic switch in B cells. J Virol 88:4811-27|
|Park, J W; Shin, M-K; Lambert, P F (2014) High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins. Oncogene 33:3383-91|
|Shrestha, Prabha; Sugden, Bill (2014) Identification of properties of the Kaposi's sarcoma-associated herpesvirus latent origin of replication that are essential for the efficient establishment and maintenance of intact plasmids. J Virol 88:8490-503|
|Vereide, D T; Seto, E; Chiu, Y-F et al. (2014) Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene 33:1258-64|
|Son, Jieun; Park, Jung Wook; Lambert, Paul F et al. (2014) Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene-induced cervical carcinogenesis in mice. Carcinogenesis 35:489-96|
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