Open Access Thesis
Date of Award
Biochemistry and Molecular Biology
Ladislau C. Kovari
HIV-1 is the causative agent of the devastating human disease Acquired Immunodeficiency Syndome (AIDS). While much progress has been made over the past two decades, HIV-1 remains a major global health concern. HIV-1 protease is 99-amino acid homodimer aspartyl protease that is essential to the life cycle of HIV. This has rendered it an attractive and very successful drug target. However, due to the high error rate of the HIV -1 reverse transcriptase, drug resistance mutations in the protease can develop very rapidly in some patients, rendering current protease inhibitors (one of the main classes of drug in common antiretroviral therapy) less effective or completely ineffective. In this thesis, we investigate the structural impact of a number of HIV-1 protease drug resistance mutations. These include L33F, which is selected for on darunavir treatment (one of the most prescirbed protease inhibitors), I47V, and V54I (which we identify as compensatory mutations involved in the tethering of the protease flaps and proper formation of the active site). A fuller understanding of the structural impact of these resistance mutations will hopefully facilitate the development of protease inhibitors that can overcome this common drug resistance.
Keusch, Bradley James, "Structure Function Studies Of Hiv-1 Protease" (2016). Wayne State University Theses. 527.