Dolutegravir potentiates platelet activation by a calcium-dependent, ionophore-like mechanism
Dolutegravir is a highly potent HIV integrase strand transfer inhibitor that is recommended for first-line anti-retroviral treatment in all major treatment guidelines. A recent study has shown that people taking this class of anti-retroviral treatment have a substantially higher risk of early-onset...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2022-12-01
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| Series: | Journal of Immunotoxicology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/1547691X.2022.2142705 |
| _version_ | 1797983852187090944 |
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| author | Morris Madzime Annette J. Theron Ronald Anderson Gregory R. Tintinger Helen C. Steel Pieter W. A. Meyer Jan G. Nel Charles Feldman Theresa M. Rossouw |
| author_facet | Morris Madzime Annette J. Theron Ronald Anderson Gregory R. Tintinger Helen C. Steel Pieter W. A. Meyer Jan G. Nel Charles Feldman Theresa M. Rossouw |
| author_sort | Morris Madzime |
| collection | DOAJ |
| description | Dolutegravir is a highly potent HIV integrase strand transfer inhibitor that is recommended for first-line anti-retroviral treatment in all major treatment guidelines. A recent study has shown that people taking this class of anti-retroviral treatment have a substantially higher risk of early-onset cardiovascular disease, a condition shown previously to be associated with increased platelet reactivity. To date, few studies have explored the effects of dolutegravir on platelet activation. Accordingly, the current study was undertaken with the primary objective of investigating the effects of dolutegravir on the reactivity of human platelets in vitro. Platelet-rich plasma, isolated platelets, or buffy coat cell suspensions prepared from the blood of healthy adults were treated with dolutegravir (2.5–10 µg/ml), followed by activation with adenosine 5’-diphosphate (ADP), thrombin, or a thromboxane A2 receptor agonist U46619. Expression of platelet CD62P (P-selectin), formation of heterotypic neutrophil:platelet aggregates, and calcium (Ca2+) fluxes were measured using flow cytometry and fluorescence spectrometry, respectively. Dolutegravir caused dose-related potentiation of ADP-, thrombin- and U46619-activated expression of CD62P by platelets, as well as a significant increases in formation of neutrophil:platelet aggregates. These effects were paralleled by a spontaneous, receptor-independent elevation in cytosolic Ca2+ that appears to underpin the mechanism by which the antiretroviral agent augments the responsiveness of these cells to ADP, thrombin and U46619. The most likely mechanism of dolutegravir-mediated increases in platelet cytosolic Ca2+ relates to a combination of lipophilicity and divalent/trivalent metal-binding and/or chelating properties of the anti-retroviral agent. These properties are likely to confer ionophore-type activities on dolutegravir that would promote movement of Ca2+ across the plasma membrane, delivering the cation to the cytosol where it would augment Ca2+-dependent intracellular signaling mechanisms. These effects of dolutegravir may lead to hyper-activation of platelets which, if operative in vivo, may contribute to an increased risk for cardiometabolic co-morbidities. |
| first_indexed | 2024-04-11T06:53:29Z |
| format | Article |
| id | doaj.art-7fa77f530f1c4a1f8353c47bb0250357 |
| institution | Directory Open Access Journal |
| issn | 1547-691X 1547-6901 |
| language | English |
| last_indexed | 2024-04-11T06:53:29Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Immunotoxicology |
| spelling | doaj.art-7fa77f530f1c4a1f8353c47bb02503572022-12-22T04:39:07ZengTaylor & Francis GroupJournal of Immunotoxicology1547-691X1547-69012022-12-011911810.1080/1547691X.2022.2142705Dolutegravir potentiates platelet activation by a calcium-dependent, ionophore-like mechanismMorris Madzime0Annette J. Theron1Ronald Anderson2Gregory R. Tintinger3Helen C. Steel4Pieter W. A. Meyer5Jan G. Nel6Charles Feldman7Theresa M. Rossouw8Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaDepartment of Internal Medicine, Faculty of Health Sciences, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaDepartment of Haematology, Faculty of Health Sciences, University of Pretoria, and Tshwane Academic Division of the National Health Laboratory Service of South Africa, Pretoria, South AfricaDepartment of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaDolutegravir is a highly potent HIV integrase strand transfer inhibitor that is recommended for first-line anti-retroviral treatment in all major treatment guidelines. A recent study has shown that people taking this class of anti-retroviral treatment have a substantially higher risk of early-onset cardiovascular disease, a condition shown previously to be associated with increased platelet reactivity. To date, few studies have explored the effects of dolutegravir on platelet activation. Accordingly, the current study was undertaken with the primary objective of investigating the effects of dolutegravir on the reactivity of human platelets in vitro. Platelet-rich plasma, isolated platelets, or buffy coat cell suspensions prepared from the blood of healthy adults were treated with dolutegravir (2.5–10 µg/ml), followed by activation with adenosine 5’-diphosphate (ADP), thrombin, or a thromboxane A2 receptor agonist U46619. Expression of platelet CD62P (P-selectin), formation of heterotypic neutrophil:platelet aggregates, and calcium (Ca2+) fluxes were measured using flow cytometry and fluorescence spectrometry, respectively. Dolutegravir caused dose-related potentiation of ADP-, thrombin- and U46619-activated expression of CD62P by platelets, as well as a significant increases in formation of neutrophil:platelet aggregates. These effects were paralleled by a spontaneous, receptor-independent elevation in cytosolic Ca2+ that appears to underpin the mechanism by which the antiretroviral agent augments the responsiveness of these cells to ADP, thrombin and U46619. The most likely mechanism of dolutegravir-mediated increases in platelet cytosolic Ca2+ relates to a combination of lipophilicity and divalent/trivalent metal-binding and/or chelating properties of the anti-retroviral agent. These properties are likely to confer ionophore-type activities on dolutegravir that would promote movement of Ca2+ across the plasma membrane, delivering the cation to the cytosol where it would augment Ca2+-dependent intracellular signaling mechanisms. These effects of dolutegravir may lead to hyper-activation of platelets which, if operative in vivo, may contribute to an increased risk for cardiometabolic co-morbidities.https://www.tandfonline.com/doi/10.1080/1547691X.2022.2142705Dolutegravirplateletscalcium fluxesCD62Pneutrophil: platelet aggregates |
| spellingShingle | Morris Madzime Annette J. Theron Ronald Anderson Gregory R. Tintinger Helen C. Steel Pieter W. A. Meyer Jan G. Nel Charles Feldman Theresa M. Rossouw Dolutegravir potentiates platelet activation by a calcium-dependent, ionophore-like mechanism Journal of Immunotoxicology Dolutegravir platelets calcium fluxes CD62P neutrophil: platelet aggregates |
| title | Dolutegravir potentiates platelet activation by a calcium-dependent, ionophore-like mechanism |
| title_full | Dolutegravir potentiates platelet activation by a calcium-dependent, ionophore-like mechanism |
| title_fullStr | Dolutegravir potentiates platelet activation by a calcium-dependent, ionophore-like mechanism |
| title_full_unstemmed | Dolutegravir potentiates platelet activation by a calcium-dependent, ionophore-like mechanism |
| title_short | Dolutegravir potentiates platelet activation by a calcium-dependent, ionophore-like mechanism |
| title_sort | dolutegravir potentiates platelet activation by a calcium dependent ionophore like mechanism |
| topic | Dolutegravir platelets calcium fluxes CD62P neutrophil: platelet aggregates |
| url | https://www.tandfonline.com/doi/10.1080/1547691X.2022.2142705 |
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