The long range goal of this project is to develop a model system for evaluation of anti-retroviral drugs and to use this system in the design and evaluation of therapeutic agents for treatment of human acquired immune deficiency syndrome (AIDS). The model which has been developed is feline immunodeficiency virus (FIV), a lentivirus associated with immunodeficiency in cats which is very similar to AIDS in humans.
The specific aims of the project are to isolate and characterize sets of azidothymidine (AZT)-resistant mutants of FIV. Attempts will also be made to isolate FIV mutants resistant to other reverse transcriptase (RT)-targeted antivirals. Analysis of these mutants will be facilitated by a focal infectivity assay for FIV developed by this laboratory. The cross-resistance of each mutant to other antivirals will be determined and experiments will be carried out to determine whether the mutants revert. Mutations in the pol (specifies viral reverse transcriptase) gene will be mapped by sequence analysis and the RT of selected mutants will be characterized. Attempts will also be made to select mutants of FIV with multiple drug resistance. The pathogenicity of selected mutants will be evaluated in specific pathogen free cats.
| Klarmann, George J; Chen, Xin; North, Thomas W et al. (2003) Incorporation of uracil into minus strand DNA affects the specificity of plus strand synthesis initiation during lentiviral reverse transcription. J Biol Chem 278:7902-9 |
