Active-Site Mutations in the South African Human Immunodeficiency Virus Type 1 Subtype C Protease Have a Significant Impact on Clinical Inhibitor Binding: Kinetic and Thermodynamic Study

Mosebi, Salerwe; Morris, Lynn; Dirr, Heini W.; Sayed, Yasien

doi:10.1128/jvi.00726-08

Cited by 38 publications

(38 citation statements)

References 28 publications

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“…16 Earlier structural and biochemical studies posit that increased flexibility is likely to contribute to less protease inhibitor susceptibility in HIV-1C SA protease. 25,26 Our molecular docking analyses further corroborate this hypothesis because both lopinavir and darunavir showed lower binding affinity to HIV-1C SE protease than to HIV-1B SE protease.…”

Section: Discussionsupporting

confidence: 62%

Virological failure in patients with HIV-1 subtype C receiving antiretroviral therapy: an analysis of a prospective national cohort in Sweden

et al. 2016

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Summary Background People with HIV-1 in low-income and middle-income countries increasingly need second-line regimens with boosted protease inhibitors. However, data are scarce for treatment response in patients with HIV-1 subtype C (HIV-1C), which is predominant in these regions. We aimed to examine factors associated with virological failure in patients in a standardised national health-care setting. Methods We analysed data for participants in InfCare HIV, a prospective national cohort that includes more than 99% of people with HIV in Sweden. We extracted data for the cohort from the InfCare HIV database on Jan 14, 2015. Baseline was initiation of antiretroviral therapy. We used logistic regression to assess factors associated with primary virological failure (failure to suppress HIV-1 within 9 months) in patients with HIV-1B and HIV-1C and calculated odds ratios (OR) for failure. We also used Cox regression models to calculate hazard ratios (HR) for time-to-secondary virological failure (detectable viral load after initial virological suppression). We did homology-based molecular modelling to assess docking. Findings We included 1077 patients with HIV-1B and 596 with HIV-1C. In multivariate regression analysis, pre-therapy higher viral load (OR 1.82, 95% CI 1.49–2.21; p<0.0001), subtype C infection (1.75, 1.06–2.88; p=0·028), and boosted protease inhibitor-based regimens (1.55, 1.45–2.11; p=0.004) were associated with increased risk of primary virological failure. Individuals with HIV-1C who were given therapy with boosted protease inhibitors had earlier time-to-secondary virological failure than did those with HIV-1B given similar regimens (adjusted HR 1.92, 95% CI 1.30–2.83; p=0.002). Molecular modelling suggested lower affinity for protease inhibitors to HIV-1C protease than to HIV-1B. Interpretation Our findings suggest an increased risk of virological failure in patients with HIV-1C, especially in those on boosted protease inhibitor-based regimens. Future studies should further dissect the biochemical and viral mechanisms of resistance to protease inhibitors in patients with non-B subtypes of HIV-1, including clinical studies to assess the efficacy of boosted protease inhibitor-based regimens in low-income and middle income countries.

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Section: Discussionsupporting

confidence: 62%

Virological failure in patients with HIV-1 subtype C receiving antiretroviral therapy: an analysis of a prospective national cohort in Sweden

et al. 2016

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“…These mutants and polymorphisms only affect the final structure or very latest stage of protein folding and fall into two categories. First is the active site mutation, D30N, which has several diverse effects (Soares et al, 2010) and particularly affects the hydrogen bonding between aspartate-30 and the drug (Ode et al, 2005;Moseby et al, 2008;Liu et al, 2011). Second are the non-active site mutations that affect the interaction between these residues and those residues lining the active site binding pocket (Ode et al, 2005(Ode et al, , 2007, mainly by small effects on late folding that distort and reduce the size of the binding pocket, affect the flap and in some cases actually restore the hydrogen binding between the drug and the protein.…”

Section: Possible Practical Applications Of Protein Folding Theorymentioning

confidence: 99%

Protein folding: Understanding the role of water and the low Reynolds number environment as the peptide chain emerges from the ribosome and folds

Sen

Voorheis

2014

Journal of Theoretical Biology

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“…Within the continent of Africa, South Africa has been shown to be at the epicentre of the epidemic as an estimated 6.1 million people (12% of total population) are living with HIV . Among different subtypes of HIV‐1, subtype C (C‐SA), is mostly prevalent in this region and this subtype accounts for approximately 50% of all HIV‐1 infections globally . C‐SA protease has eight point mutations compared to subtype B and these are T12S, I15V, L19I, M36I, R41K, H69K, L89M and I93L .…”

Section: Introductionmentioning

confidence: 99%

“…The fulcrum, hinge and cantilever regions consist of six mutations (T12S, I15V, L19I, M36I, R41K and H69K) that distinguish C‐SA from subtype B . The I15V is a part of the hydrophobic core and the L19I mutation is believed to contribute to the rearrangement of hydrophobic interactions in the hydrophobic core .…”

Section: Introductionmentioning

confidence: 99%

Exploring the flap dynamics of the South African HIV subtype C protease in presence of FDA‐approved inhibitors: MD study

et al. 2018

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HIV-1 protease (HIV PR) is considered as one of the most attractive targets for the treatment of HIV and the impact of flap dynamics of HIV PR on the binding affinities of protease inhibitors (PIs) is a crucial ongoing research field. Recently, our research group evaluated the binding affinities of different FDA approved PIs against the South African HIV-1 subtype C (C-SA) protease (PR). The CSA-HIV PR displayed weaker binding affinity for most of the clinical PIs compared to HIV-1 B subtype for West and Central Europe, the Americas. In the current work, the flap dynamics of four different systems of HIV-1 C-SA PR complexed to FDA approved second generation PIs and its impact on binding was explored over the molecular dynamic trajectories. It was observed that the interactions of the selected drugs with the binding site residues of the protease may not be the major contributor for affinity towards PIs. Various post-MD analyses were performed, also entropic contributions, solvation free energies and hydrophobic core formation interactions were studied to assess how the flap dynamics of C-SA PR which is affected by such factors. From these contributions, large van der Waals interactions and low solvation free energies were found to be major factors for the higher activity of ATV against C-SA HIV PR. Furthermore, a comparatively stable hydrophobic core may be responsible for higher stability of the PR flaps of the ATV complex. The outcome of this study provides significant guidance to how the flap dynamics of C-SA PR is affected by various factors as a result of the binding affinity of various protease inhibitors. It will also assist with the design of potent inhibitors against C-SA HIV PR that apart from binding in the active site of PR can interacts with the flaps to prevent opening of the flaps resulting in inactivation of the protease.

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Active-Site Mutations in the South African Human Immunodeficiency Virus Type 1 Subtype C Protease Have a Significant Impact on Clinical Inhibitor Binding: Kinetic and Thermodynamic Study

Cited by 38 publications

References 28 publications

Virological failure in patients with HIV-1 subtype C receiving antiretroviral therapy: an analysis of a prospective national cohort in Sweden

Virological failure in patients with HIV-1 subtype C receiving antiretroviral therapy: an analysis of a prospective national cohort in Sweden

Protein folding: Understanding the role of water and the low Reynolds number environment as the peptide chain emerges from the ribosome and folds

Exploring the flap dynamics of the South African HIV subtype C protease in presence of FDA‐approved inhibitors: MD study

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