Effects of Natural Polymorphisms of non-B HIV-1 Protease on Protein Conformations

Abstract

HIV-1 protease (PR) is essential to the maturation of HIV-1 virus as it post-translationally cleaves the viral polyproteins gag and gag-pol. Inhibition of HIV-1 PR lead to non-infectious immature virus. This makes HIV-1 PR a drug target for HIV infection. The flaps of HIV-1 PR play an important role in its catalytic activity as they control access of substrate as well as inhibitor to the catalytic pocket of the protease. The flaps of HIV-1 PR adopt different conformations: closed, semi-open, wide-open, and curled-open [1]. Our previous study suggests natural polymorphisms can affect conformational ensembles of the protease [2]. In this study, double electron-electron resonance (DEER) is utilized to study how natural polymorphisms affect protein conformational ensembles in non-B HIV-1 PR variants including subtypes D, H, and F, and CRFs AC, AG, and BF. Most of these variants showed conformational ensembles similar to that of multidrug resistant variant. Darunavir, the most potent protease inhibitor to date, was unable to shift flap conformation of CRF_AC to closed conformation which is indicative of drug resistance.