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bioRxiv · 10.1101/2023.05.17.541113

Altered glucose utilization and disrupted mitochondrial homeostasis in CD4+ T cells from HIV-positive women on combination anti-retroviral therapy

Akiso, M.·Ameka, M.·Naidoo, K.·Langat, R.·Kombo, J.·Sikuku, D.·Ndung'u, T.·Altfeld, M.·Anzala, O.·Mureithi, M.
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Abstract

BackgroundFor optimal functionality, immune cells require a robust and adaptable metabolic program that is fueled by dynamic mitochondrial activity. In this study, we investigate the metabolic alterations occurring in immune cells during HIV infection and antiretroviral therapy by analyzing the uptake of metabolic substrates and mitochondrial homeostasis. By delineating changes in immune cell metabolic programming during HIV, we may identify novel potential therapeutic targets to improve antiviral immune responses. MethodsWhole blood was drawn from HIV uninfected female volunteers and women with chronic HIV infection on combination antiretroviral therapy. Peripheral blood mononuclear cells-derived immune cells were directly incubated with different fluorescent markers: FITC-2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose), FITC-BODIPY (4,4-Difluoro-5,7-Dimethyl-4-Bora-3a,4a-Diaza-s-Indacene-3-Hexadecanoic Acid), FITC-MitoTracker Green and APC-MitoTracker Deep Red. The uptake of glucose and fats and the mitochondrial mass and potential were measured using flow cytometry. All values are reported quantitatively as geometric means of fluorescence intensity. ResultsDuring chronic HIV infection, cellular uptake of glucose increases in HIV+ dendritic cells (DCs) in particular. CD4+ T cells had the lowest uptake of glucose and fats compared to all other cells regardless of HIV status, while CD8+ T cells took up more fatty acids. Interestingly, despite the lower utilization of glucose and fats in CD4+ T cells, mitochondrial mass increased in HIV+ CD4+ T cells compared to HIV negative CD4+ T-cells. HIV+ CD4+ T cells also had the highest mitochondrial potential. ConclusionsSignificant disparities in the utilization of substrates by leukocytes during chronic HIV/cART exist. Innate immune cells increased utilization of sugars and fats while adaptive immune cells displayed lower glucose and fat utilization despite having a higher mitochondrial activity. Our findings suggest that cART treated HIV-infected CD4+ T cells may prefer alternative fuel sources not included in these studies. This underscores the importance of understanding the metabolic effects of HIV treatment on immune function.

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Akiso, M., Ameka, M., Naidoo, K., Langat, R., Kombo, J., Sikuku, D., Ndung'u, T., Altfeld, M., Anzala, O., Mureithi, M.. 2023-05-20. Altered glucose utilization and disrupted mitochondrial homeostasis in CD4+ T cells from HIV-positive women on combination anti-retroviral therapy. https://doi.org/10.1101/2023.05.17.541113

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