Abstract
Understanding the underlying molecular interaction during a therapy switch from lopinavir (LPV) to darunavir (DRV) is essential to achieve long-term virological suppression. We investigated the kinetic and structural characteristics of multidrug-resistant South African HIV-1 subtype C protease (HIV-1 PR) during therapy switch from LPV to DRV using enzyme activity and inhibition assay, fluorescence spectroscopy, and molecular dynamic simulation. The HIV-1 protease variants were from clinical isolates with a combination of drug resistance mutations; MUT-1 (M46I, I54V, V82A, and L10F), MUT-2 (M46I, I54V, L76V, V82A, L10F, and L33F), and MUT-3 (M46I, I54V, L76V, V82A, L90M, and F53L). Enzyme kinetics analysis shows an association between increased relative resistance to LPV and DRV with the progressive decrease in the mutant HIV-1 PR variants’ catalytic efficiency. A direct relationship between high-level resistance to LPV and intermediate resistance to DRV with intrinsic changes in the three-dimensional structure of the mutant HIV-1 PR as a function of the multidrug-resistance mutation was observed. In silico analysis attributed these structural adjustments to the multidrug-resistance mutations affecting the LPV and DRV binding landscape. Though DRV showed superiority to LPV, as a lower concentration was needed to inhibit the HIV-1 PR variants, the inherent structural changes resulting from mutations selected during LPV therapy may dynamically shape the DRV treatment outcome after the therapy switch.
Highlights
HIV-1 infection remains a serious public health problem, with about 38 million infected people at the end of 2019 [1]
We found that the combination of the mutations harbored by the mutant HIV-1 PR variants significantly impacted enzyme catalytic activity
The authors of this study showed that the accumulation of multidrug-resistant mutations causes inherent changes in the structures of HIV-1 PR, resulting in HIV-1 PR variants with increased conformational flexibility and an open conformation
Summary
HIV-1 infection remains a serious public health problem, with about 38 million infected people at the end of 2019 [1]. The global HIV-1 epidemic burden rests heavily on countries in sub-Saharan Africa [2]. South Africa remains the global epicenter of the HIV-1 epidemic, with the pandemic dominated by the HIV-1 subtype C [3,4]. The standard treatment of HIV-1 infection is highly active antiretroviral therapy (HAART) [5]; HAART has greatly improved the clinical outcome of HIV-infected persons since its introduction [6]. The increasing cases of virological failure associated with first and second-line antiretroviral therapy (ART) present a significant clinical challenge for patient management in resource-constrained settings [7]
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