Browsing by Author "Mikasi, Sello Given"

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    Drug resistance mutations against protease, reverse transcriptase and integrase inhibitors in people living with HIV-1 receiving boosted protease inhibitors in South Africa
    (Frontiers Media S.A., 2020) Cloete, Ruben; Obasa, Adetayo Emmanuel; Mikasi, Sello Given
    The South African national combination antiretroviral therapy (cART) roll-out program started in 2006, with over 4.4 million people accessing treatment since it was first introduced. HIV-1 drug resistance can hamper the success of cART. This study determined the patterns of HIV-1 drug-resistance associated mutations (RAMs) in People Living with HIV-1 (PLHIV-1). Receiving first (for children below 3 years of age) and second-line (for adults) cART regimens in South Africa. During 2017 and 2018, 110 patients plasma samples were selected, 96 samples including those of 17 children and infants were successfully analyzed. All patients were receiving a boosted protease inhibitor (bPI) as part of their cART regimen. The viral sequences were analyzed for RAMs through genotypic resistance testing. We performed genotypic resistance testing (GRT) for Protease inhibitors (PIs), Reverse transcriptase inhibitors (RTIs) and Integrase strand transfer inhibitors (InSTIs). Viral sequences were subtyped using REGAv3 and COMET. Based on the PR/RT sequences, HIV-1 subtypes were classified as 95 (99%) HIV-1 subtype C (HIV-1C) while one sample as 02_AG.
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    HIV-1 diversity and the implementation of integrase strand-transfer inhibitors as part of combination antiretroviral therapy
    (SAMA, 2020) Cloete, Ruben; Mikasi, Sello Given; Ikomey, George Mondinde
    : The integrase (IN) strand-transfer inhibitor (InSTI) dolutegravir (DTG) is now recommended by the World Health Organization as part of salvage and/or first-line combination antiretroviral therapy (cART).[1] DTG has a high genetic barrier against developing resistance and is effective against all strains that previously exhibited resistance-associated mutations (RAMs) against other cART regimens.[2] Recommendations to use DTG were delayed owing to preliminary findings from Botswana that indicated potential safety concerns in pregnancy, with a small increased risk of neural tube defects.[3] Studies that investigated the safety and efficacy of DTG now support its use in all populations, including pregnant women and those of childbearing potential
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    Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C integrase-dolutegravir binding
    (Public Library of Science, 2020) Chitongo, Rumbidzai; Obasa, Adetayo Emmanuel; Mikasi, Sello Given
    Resistance associated mutations (RAMs) threaten the long-term success of combination antiretroviral therapy (cART) outcomes for HIV-1 treatment. HIV-1 Integrase (IN) strand transfer inhibitors (INSTIs) have proven to be a viable option for highly specific HIV-1 therapy. The INSTI, Dolutegravir is recommended by the World Health Organization for use as first-line cART. This study aims to understand how RAMs affect the stability of IN, as well as the binding of the drug Dolutegravir to the catalytic pocket of the protein. A homology model of HIV-1 subtype C IN was successfully constructed and validated. The site directed mutator webserver was used to predict destabilizing and/or stabilizing effects of known RAMs while FoldX confirmed any changes in protein energy upon introduction of mutation. Also, interaction analysis was performed between neighbouring residues. Three mutations known to be associated with Raltegravir, Elvitegravir and Dolutegravir resistance were selected; E92Q, G140S and Y143R, for molecular dynamics simulations. The structural quality assessment indicated high reliability of the HIV-1C IN tetrameric structure, with more than 90% confidence in modelled regions. Change in free energy for the three mutants indicated different effects, while simulation analysis showed G140S to have the largest affect on protein stability and flexibility.
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    Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors
    (MPDI, 2020) Isaacs, Darren; Mikasi, Sello Given; Obasa, Adetayo Emmanuel
    The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.