Pro-inflammatory interactions of dolutegravir with human neutrophils in an in vitro study

Show simple item record Theron, Annette J. Anderson, Ronald Madzime, Morris Rossouw, Theresa M. Steel, Helen C. Meyer, Pieter Willem Adriaan Cholo, Moloko C. Kwofie, Luyanda Laura Illicia Feldman, Charles Tintinger, Gregory 2023-09-21T09:38:41Z 2023-09-21T09:38:41Z 2022-12-19
dc.description DATA AVAILABILITY STATEMENT : Data can be made available upon request. en_US
dc.description.abstract There is increasing awareness of an association between the uptake of the HIV integrase inhibitor, dolutegravir, in first-line antiretroviral regimens with unusual weight gain and development of the metabolic syndrome, particularly in African women. Although seemingly unexplored, the development of systemic inflammation linked to the putative pro-inflammatory activity of dolutegravir represents a plausible pathophysiological mechanism of this unusual weight gain. This possibility was explored in the current study undertaken to investigate the effects of dolutegravir (2.5–20 g/mL) on several pro-inflammatory activities of neutrophils isolated from the blood of healthy, adult humans. These activities included the generation of reactive oxygen species (ROS), degranulation (elastase release) and alterations in the concentrations of cytosolic Ca2+ using chemiluminescence, spectrophotometric and fluorimetric procedures, respectively. Exposure of neutrophils to dolutegravir alone resulted in the abrupt, dose-related, and significant (p < 0.0039–p < 0.0022) generation of ROS that was attenuated by the inclusion of the Ca2+-chelating agent, EGTA, or inhibitors of NADPH oxidase (diphenyleneiodonium chloride, DPI), phospholipase C (U733122), myeloperoxidase (sodium azide) and phosphoinositol-3-kinase (wortmannin). In addition, exposure to dolutegravir augmented the release of elastase by stimulus-activated neutrophils. These pro-inflammatory effects of dolutegravir on neutrophils were associated with significant, rapid, and sustained increases in the concentrations of cytosolic Ca2+ that appeared to originate from the extracellular compartment, seemingly consistent with an ionophore-like property of dolutegravir. These findings are preliminary and necessitate verification in the clinical setting of HIV infection. Nevertheless, given the complex link between inflammation and obesity, these pro-inflammatory interactions of dolutegravir with neutrophils may contribute to unexplained weight gain, possibly via the development of insulin resistance. en_US
dc.description.department Immunology en_US
dc.description.department Internal Medicine en_US
dc.description.librarian am2023 en_US
dc.description.sponsorship The National Health Laboratory Research Trust of South Africa and the National Research Foundation of South Africa. en_US
dc.description.uri en_US
dc.identifier.citation Theron, A.J.; Anderson, R.; Madzime, M.; Rossouw, T.M.; Steel,V.H.C.; Meyer, P.W.A.; Cholo, M.C.; Kwofie, L.L.I.; Feldman, C.; Tintinger, G.R. Pro-Inflammatory Interactions of Dolutegravir with Human Neutrophils in an In Vitro Study. Molecules 2022, 27, 9057. en_US
dc.identifier.issn 1420-3049 (online)
dc.identifier.other 10.3390/molecules27249057
dc.language.iso en en_US
dc.publisher MDPI en_US
dc.rights © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. en_US
dc.subject Cytosolic calcium en_US
dc.subject Elastase en_US
dc.subject Ionophore en_US
dc.subject Pro-inflammatory activity en_US
dc.subject Human immunodeficiency virus (HIV) en_US
dc.subject Dolutegravir (DTG) en_US
dc.subject SDG-03: Good health and well-being en_US
dc.title Pro-inflammatory interactions of dolutegravir with human neutrophils in an in vitro study en_US
dc.type Article en_US

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