Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Metabolism. 2023 Apr;141:155395. doi: 10.1016/j.metabol.2022.155395. Epub 2023 Jan 14.
Mitochondria regulate immune and organ function. It is unknown whether higher intracellular drug levels observed in peripheral blood mononuclear cells (PBMCs) treated with tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF) may alter mitochondrial function and energy production in immune cells in HIV patients.
Cellular bioenergetics were determined in PBMCs from HIV-1 participants exposed to TAF versus TDF in vitro, at a comparable concentration to a clinically relevant plasma exposure. A decrease in cellular oxygen consumption rate (OCR) at baseline (basal-OCR) and under cellular stress (max-OCR) may suggest mitochondrial dysfunction. We also assessed the in vivo impact of TAF vs TDF on OCR in PBMCs from 26 people with HIV (PWH) interchanged from TDF-based to TAF-based antiretroviral therapy (ART) over a 9-month period in the setting of an open label clinical trial. The Wilcoxon and Mann Whitney tests were used for comparison of continuous variables.
PBMCs from HIV-1 participants exposed in vitro to a concentration of 0.12-3.3 μM for TAF and TDF at 2 and 24 h, reduced basal and maximal OCR compared to vehicle control. Switch studies of antivirals (TAF vs TDF) within the same PWH showed that TAF-based ART was associated with reduced OCR compared to TDF-based ART in PBMCs. We observed that TAF-treated PBMCs selectively relied more on glucose/pyruvate supply rather than fatty acid to fuel their mitochondria.
Compared to TDF, TAF may alter bioenergetics in immune cells from PWH in vitro and in vivo. The clinical significance in terms of the differential impact caused by TAF versus TDF on mitochondrial function and energy production in immune cells, a regulator of immune function, requires further studied in HIV, preexposure prophylaxis and hepatitis B.
线粒体调节免疫和器官功能。目前尚不清楚与富马酸替诺福韦二吡呋酯（TDF）相比，替诺福韦艾拉酚胺（TAF）在治疗外周血单个核细胞（PBMC）时观察到的细胞内药物水平升高是否会改变 HIV 患者免疫细胞中的线粒体功能和能量产生。
在体外，将 HIV-1 参与者暴露于 TAF 与 TDF 时，在与临床相关的血浆暴露相当的浓度下，测定 PBMC 中的细胞生物能量。细胞耗氧量率（OCR）基线（基础-OCR）和细胞应激下（最大-OCR）的降低可能表明线粒体功能障碍。我们还评估了 TAF 与 TDF 在 26 名接受 TDF 转为 TAF 基于抗逆转录病毒治疗（ART）的 HIV 感染者（PWH）的 PBMC 中的体内影响，这是在一项开放标签临床试验中进行的，为期 9 个月。Wilcoxon 和 Mann Whitney 检验用于比较连续变量。
在体外，将 HIV-1 参与者暴露于 0.12-3.3μM TAF 和 TDF 浓度 2 和 24 小时，与载体对照相比，PBMC 的基础和最大 OCR 降低。在同一 PWH 中抗病毒药物的转换研究（TAF 与 TDF）表明，与 TDF 相比，TAF 基于 ART 与 PBMC 中的 TDF 相比，OCR 降低。我们观察到 TAF 处理的 PBMC 选择性地更多地依赖于葡萄糖/丙酮酸供应，而不是脂肪酸来为其线粒体提供燃料。
与 TDF 相比，TAF 可能会改变体外和体内来自 PWH 的免疫细胞的生物能量。TAF 与 TDF 对免疫细胞线粒体功能和能量产生的影响差异的临床意义，作为免疫功能的调节剂，需要在 HIV、暴露前预防和乙型肝炎中进一步研究。
