Characterizing protease inhibitor failure in HIV-1 subtype C, using ultra deep pyro-sequencing and homology modelling.
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Date
2015
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Abstract
The extensive roll-out of combination antiretroviral therapy (cART) has significantly
improved the life expectancy for HIV-1 infected individuals in South Africa. Despite
the inclusion of potent Protease Inhibitors (PIs) in second-line cART, many patients
still fail treatment. The extent to which PI resistance contributes to treatment failure
is not completely clear. In this study we report the prevalence of PI mutations
amongst individuals failing a second-line Lopinavir (LPV/r) inclusive regimen. We
also investigated if low frequency minority variants at LPV/r failure influence
Darunavir (DRV/r) failure in a subset of patients using Ultra Deep Pyro-sequencing.
Structural changes at DRV/r failure were investigated using Homology modeling.
Models were constructed using the SWISS-MODEL webserver and visualized in
Chimera v1.8.1. Darunavir was docked into each of the structures using the CLC
Drug Discovery workbench ™ and Molecular Dynamics simulations was performed
using the AMBER12 package. Our study reports a 24% prevalence of PI resistance
mutations, slightly higher than other studies. A distinct pattern of PI resistance
mutations was found: M46I+I54V+L76V+V82A, present in 13/37 (35%) of those
with PI mutations. Darunavir resistance mutations detected following DRV/r failure
included V11I, V32I, L33F and I54L. There were no minority variants detected at
LPV/r failure that could have influenced DRV/r failure. Distinct conformational
changes were evident in both the LPV/r-resistant and DRV/r-resistant model.
Molecular docking showed that the inhibitory potency of DRV was lowered in the
mutated DRV/r-resistant model and to a lesser extent in the LPV/r-resistant model.
These results show that resistance mutations greatly contribute to DRV drug
susceptibility. This work will contribute to the clinical management of patients failing
treatment and will also assist in the design of new and improved ARVs.
Description
Master of Medical Sciences in Virology. University of KwaZulu-Natal, Medical School 2015.
Keywords
Protease inhibitors., HIV infections -- Treatment., AIDS-related complex., Viruses -- Variation., Theses -- Virology., HIV-1 subtype C.