The long range objective of this work is to understand the mechanisms by which lentiviruses become resistant to antiviral drugs and to utilize this information to help develop improved strategies for chemotherapy of the acquired immune deficiency syndrome (AIDS). This information should be particularly important for development of approaches to combat the emergence of drug-resistance. We have developed model systems using feline immunodeficiency virus (FIV) for studies of resistance to AIDS chemotherapy. These systems have proven extremely useful and versatile for selection and characterization of FIV mutants resistant to nucleoside analogs. The work proposed here will extend these systems to address several important aspects of resistance: 1) Preliminary data suggest that factors other than reverse transcriptase (RT) are involved in resistance to 3'-azido-3'-deoxythymidine (AZT). The non-RT factors involved in AZT- resistance will be identified and characterized. 2) The effect of drug concentration on the types of drug-resistant mutants that arise will be determined. In particular, the emergence of mutants in the presence of subinhibitory concentrations of drugs will be studied. 3) The FIV model will be improved by introduction of the human immunodeficiency virus type 1 (HIV-1) RT into FIV. The resulting chimeric virus will enable studies of this important enzyme in our versatile model system. 4) An exciting new class of oligonucleotide (RNA) inhibitors that are targeted against RT will be studied. Experiments will be carried out to select and characterize mutants resistant to these inhibitors. Approaches will be initiated using these inhibitors to evaluate strategies that are designed to combat resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028189-11
Application #
2696852
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1988-09-30
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
2000-05-31
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Davis
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618