Dolutegravir-containing HIV therapy reversibly alters mitochondrial health and morphology in cultured human fibroblasts and PBMC.
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Abstract
Given the success of antiretrovirals (ARV)s in treating HIV viremia, drug toxicity remains an area of interest in HIV research. Despite newer integrase strand transfer inhibitors (InSTIs), such as dolutegravir (DTG) and raltegravir (RAL), having excellent clinical tolerance, there is emerging evidence of off-target effects and toxicities. Although limited in number, recent reports have highlighted the vulnerability of mitochondria to these toxicities. The aim of the present study is to quantify changes in cellular and mitochondrial health following exposure to current cART regimens at pharmacological concentrations. A secondary objective is to determine whether any cART-associated toxicities would be modulated by human telomerase reverse transcriptase (hTERT).We longitudinally evaluated markers of cellular (cell count, apoptosis), and mitochondrial health (mitochondrial reactive oxygen species [mtROS], mitochondrial membrane potential and mitochondrial mass) by flow cytometry in WI-38 human fibroblast with differing hTERT expression/localisation, and PBMC. This was done after nine days of exposure to, and six days following the removal of, seven current cART regimens, including three that contained DTG. Mitochondrial morphology was assessed by florescence microscopy and quantified using a recently developed deep learning-based pipeline.Exposure to DTG-containing regimens increased apoptosis, mtROS, mitochondrial mass, induced more fragmented mitochondrial networks compared to non DTG-containing regimens, including a RAL-based combination. These effects were unmodulated by telomerase expression. All effects were fully reversible following removal of drug pressure.Taken together, our observations indicate that DTG-containing regimens negatively impact cellular and mitochondrial health and may be more toxic to mitochondria, even among the generally well-tolerated InSTI-based cART.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.