Immunocompatibility Group, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, Liverpool, UK; Centre of Excellence for Long-Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, UK.
Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, Liverpool, UK.
Biomed Pharmacother. 2022 Jun;150:112999. doi: 10.1016/j.biopha.2022.112999. Epub 2022 Apr 20.
SLC2A1 mediates glucose cellular uptake; key to appropriate immune function. Our previous work has shown efavirenz and lopinavir exposure inhibits T cell and macrophage responses, to known agonists, likely via interactions with glucose transporters. Using human cell lines as a model, we assessed glucose uptake and subsequent bioenergetic profiles, linked to immunological responses. Glucose uptake was measured using 2-deoxyglucose as a surrogate for endogenous glucose, using commercially available reagents. mRNA expression of SLC transporters was investigated using qPCR TaqMan™ gene expression assay. Bioenergetic assessment, on THP-1 cells, utilised the Agilent Seahorse XF Mito Stress test. In silico analysis of potential interactions between SLC2A1 and antiretrovirals was investigated using bioinformatic techniques. Efavirenz and lopinavir exposure was associated with significantly lower glucose accumulation, most notably in THP-1 cells (up to 90% lower and 70% lower with efavirenz and lopinavir, respectively). Bioenergetic assessment showed differences in the rate of ATP production (J); efavirenz (4 μg/mL), was shown to reduce J by 87% whereas lopinavir (10 μg/mL), was shown to increase the overall J by 77%. Putative in silico analysis indicated the antiretrovirals, apart from efavirenz, associated with the binding site of highest binding affinity to SLC2A1, similar to that of glucose. Our data suggest a role for efavirenz and lopinavir in the alteration of glucose accumulation with subsequent alteration of bioenergetic profiles, supporting our hypothesis for their inhibitory effect on immune cell activation. Clarification of the implications of this data, for in vivo immunological responses, is now warranted to define possible consequences for these, and similar, therapeutics.
SLC2A1 介导葡萄糖细胞摄取；是适当免疫功能的关键。我们之前的工作表明，依非韦伦和洛匹那韦暴露会抑制 T 细胞和巨噬细胞对已知激动剂的反应，这可能是通过与葡萄糖转运蛋白相互作用实现的。我们使用人细胞系作为模型，评估了葡萄糖摄取以及随后与免疫反应相关的生物能量谱。使用商业上可获得的试剂，使用 2-脱氧葡萄糖作为内源性葡萄糖的替代物来测量葡萄糖摄取。使用 qPCR TaqMan™基因表达测定法研究 SLC 转运蛋白的 mRNA 表达。在 THP-1 细胞上进行生物能量评估，利用安捷伦 Seahorse XF Mito Stress 测试。使用生物信息学技术研究了 SLC2A1 与抗逆转录病毒之间潜在相互作用的计算机分析。依非韦伦和洛匹那韦暴露与葡萄糖积累明显降低有关，在 THP-1 细胞中尤为明显（依非韦伦和洛匹那韦分别降低了高达 90%和 70%）。生物能量评估显示了 ATP 产生率（J）的差异；依非韦伦（4μg/mL）被证明降低了 87%，而洛匹那韦（10μg/mL）被证明总体上增加了 77%。推测的计算机分析表明，除了依非韦伦之外，这些抗逆转录病毒与 SLC2A1 的结合部位具有最高的结合亲和力，类似于葡萄糖。我们的数据表明，依非韦伦和洛匹那韦在改变葡萄糖积累方面发挥作用，随后改变生物能量谱，支持我们关于它们对免疫细胞激活的抑制作用的假设。现在需要澄清这些数据对体内免疫反应的影响，以确定这些和类似治疗方法的可能后果。
