Human papillomaviruses (HPVs) type 16, 18, 31 and 33 are causally associated with cancer of the genital mucosa in humans. Neoplastic progression from benign hyperplasia to carcinoma involves the loss of autonomous replication of the viral plasmid DNA and places the expression of the viral oncogenes under cellular control. During normal infection wit HPVs, which cause benign proliferative lesions, the viral DNA establishes itself as a low copy number nuclear plasmid in basal keratinocytes of the host epithelium. Vegetative amplification of the viral genomes and the production of progeny virions are observed only when the basal keratinocytes undergo differentiation. This proposal outline a course of study that will (i) lead to the identification of DNA sequence elements th function in the maintenance of the viral plasmids in persistently infected keratinocytes, (ii) determine the DNA sequence requirements of vegetative viral DNA amplification in differentiating cells. In the proposed experiments, deletion mutations in the background of the viral genome will be used to map new genetic elements. In addition, the known elements of the transient replication origin will be inactivated with specific point mutations. All mutated viral DNAs will be transfected into human keratinocytes that provide the required replication functions from endogenous HPV31 DNA. Sable replication and DNA amplifcation will be assessed by HPV31-specifed Southern and in situ hybridization.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA073087-01A1
Application #
2416846
Study Section
Special Emphasis Panel (ZRG5-EVR (01))
Project Start
1998-01-31
Project End
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611