Immunometabolism in chronic HIV-1 infection

Metabolism plays a key role in a cell’s ability to maintain their viability and fulfil their effector functions. It has been shown that cells in chronically HIV-infected individuals become exhausted and undergo a progressive loss of hierarchical functions, but the changes in their cellular metabolism remain unclear. Discovering and finding potential changes in the metabolism might offer a new potential targets in cure of the infection. To understand changes in immune metabolism in subjects with chronic HIV infection, we firstly assessed differences in metabolism of different cell subsets. We described that individual immune cell subsets have quite distinct metabolic requirements. We showed that the metabolism of T cells, in particular CD4 T cells is significantly higher compared to B cells or NK cells. When we compared the metabolic parameters between chronically HIV-infected treatment-naïve and HIV negative individuals, we observed that the HIV infection negatively affects metabolism, mainly cellular respiration. This was in negative correlation with immune activation and exhaustion. The progression of HIV infection and immune dysfunction can be slowed down or even reverted with appropriate ART. We analyzed whether is metabolism of immune cells restored after ART initiation. CD8 T cells, NK cells and B cells were able to perform both glycolysis and oxidative phosphorylation compared to healthy subjects, however CD4 T cells maintained low respiration. To see which class or better which drug is responsible for the metabolic shut down, we performed set of in vitro experiments when we treated CD4 T cells with individual drug regimens. We saw a very strong impact of two drugs from INSTI class – DLG and EVG. They both not only significantly reduced cellular respiration but also weaken the ability of the cells to secrete cytokines. Due to the fact that EVG was developed from quinolone antibiotics which were shown to cause mitochondrial toxicity, we decided to see whether there are some physiological changes in mitochondria of our treated cells. We found, that the cells which were treated with either EVG or DLG significantly increased the mitochondrial mass and at the same time also mtROS. In this case, more mitochondria does not mean better respiration of the cells. Increased mtROS indicates that the cell might have more mitochondria, but these are not functional. Taken together, our data demonstrate a substantial disruption in the metabolic activity of lymphocytes during chronic HIV infection that is restored through antiretroviral therapy. However, two INSTI, DLG and EVG, diminish the metabolic activity in CD4 T cells, leading to a switch in functionality and impairment of overall function.


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