Hepatitis B viruses comprise the family hepadnaviridae. Hepatitis B (HBV) in humans is responsible for a range of clinical infections varying from acute fulminant hepatitis to chronic hepatitis B infections. The development of cirrhosis and primary hepatic cancer is directly linked to this chronic infection. Currently no satisfactory treatment exists. The chronicity and high infectivity of the virus are the reason that it remains such a major public health problem. Hepadnaviridae are unique and novel amongst viruses in that, although they are DNA viruses, they replicate via an RNA intermediate. The protein directly responsible for this reverse transcription is an impressive example of the nature's efficiency. With only 3-4 ORFs, this protein the polymerase, is not only responsible for the transcription of the RNA intermediate but most unusually, it primes the nucleic acid replication i.e. it primes the same reaction it catalyzes. It also plays a key role in the encapsidation of the virus. A central mechanism in the function of this protein is its binding to the pregenomic RNA, via a stem loop (SL) structure. The proposed study aims to determine exactly how the protein binds to the RNA SL using duck hepatitis B virus. The polymerase protein itself, despite many attempts, has not been successfully purified in a functional form. This has prevented any data to be gathered on the structure of the protein. It is proposed to overcome this difficulty by investigating the tow domains involved in binding separately. In particular the terminal protein domain will be studied both in terms of RNA binding and its structure determined. The reverse transcriptase domain is the other domain that will be studies. In this application, the candidate hopes to provide further valuable insight into protein RNA interaction and binding and help to elucidate a critical step in the replication of the hepatitis viruses, thereby providing the foundation for the rational development of inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI001456-02
Application #
2671452
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Project Start
1997-08-01
Project End
2002-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294