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IN VITRO IMPACT OF TAF ON
MITOCHONDRIAL FUNCTION IN IMMUNE CELLS
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CROI 2020
Reported by Jules Levin
E. Ritou1, R. Heymans1, T. Kelesidis1 1. David Geffen School of Medicine at University of California - Los Angeles
Program Abstract
Mitochondrial dysfunction has been involved in toxicity of antiretrovirals such as Zalcitabine (ddC). Markedly lower plasma levels of tenofovir (TFV) are thought to lead to the more favorable bone and renal safety profile of tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF). It is unknown whether an increase in intracellular levels of the active metabolite, tenofovir-diphosphate (TFV-DP) with TAF (compared to TDF) may alter mitochondria. This study was designed to address whether TAF affects in vitro mitochondrial membrane potential (MMP), a direct measure of the state of energization of the mitochondria, in peripheral blood mononuclear cells (PBMCs).
PBMCs were isolated from healthy 18-40 years old participants (n=10). PBMCs were incubated for 2-hour with TDF and/or TAF at concentrations that model clinically relevant plasma exposure. ddC was used as positive control. We used flow cytometry and the dye Tetramethylrhodamine ethyl ester (TMRE) to quantify the MMP in immune cells. Wilcoxon tests were used for statistical comparison between groups.
After 2 hours of in vitro exposure of PBMCs to 0.12-3.3 M TAF, TDF and ddC, 3.3 M ddC and 0.12, 3.3 M TDF did not affect the median fluorescence intensity (MFI) of TMRE in CD3+, CD4+, CD8+ T cells and CD14+ cells compared to DMSO control. 3.3 M TAF increased the MFI of TMRE in CD3+ T cells and in CD14+ monocytes compared to DMSO control (p<0.05). 3.3 M TAF increased the MFI of TMRE in CD8+ T cells compared to ddC (p<0.05). 2 hours of in vitro exposure of primary PBMCs to 0.12-3.3 M TAF did not affect the MFI of TMRE in CD4+ T cells and increased the MFI of TMRE compared to TDF in CD3+ T cells and CD14+ monocytes (Figure).
We did not find any evidence of in vitro mitochondrial toxicity (reduction in MMP) with TAF. TAF may increase in vitro the MMP in resting PBMC as early as 2 hours. This concentration dependent effect was more prominent in monocytes compared to T cells. The clinical relevance of these in vitro findings is unknown. The effect of TAF on mitochondrial function in chronic treated HIV should be further explored in patients switching from TDF to TAF regimens.
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