HIV - 1 Protease: Insights into Drug Resistance Development

Abstract

Amino acid changes within HIV protease or its substrate that decrease the susceptibility to protease inhibitors represent a highly complex issue still not yet fully understood. Various mechanisms by which this often complicated pattern of mutations influence drug binding needs to be analyzed on a molecular level by a series of methods including experiments with recombinant viruses, biochemical enzyme analysis, structural and thermodynamical studies or molecular dynamics. Each result may help to complete the overall picture of protease inhibitor resistance evolution and therefore contribute to the design of more powerful 3rd generation HIV/AIDS drugs. This thesis presents several analyses of HIV resistance development on molecular level. We have focused on the nelfinavir resistance pathway, lopinavir mutation score, emergence of amino acid insertions in HIV protease gene and their contribution to protease inhibitor resistance and finally we analyzed a highly mutated protease species isolated from patients failing darunavir therapy. Since we are able to accomplish a wide combination of techniques, we could explain and put together some pieces of viral evolution considering the final steps of HIV life cycle and also provide knowledge necessary for novel inhibitor design. Aims of the Project There were..