Beyond the polymerase-γ theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity

Abstract

Use of some HIV-1 nucleoside reverse transcriptase inhibitors (NRTI) is associated with severe adverse events. However, the exact mechanisms behind their toxicity has not been fully understood. Mitochondrial dysfunction after chronic exposure to specific NRTIs has predominantly been assigned to mitochondrial polymerase-γ inhibition by NRTIs. However, an increasing amount of data suggests that this is not the sole mechanism. Many NRTI induced adverse events have been linked to the incurrence of oxidative stress, although the causality of events leading to reactive oxygen species (ROS) production and their role in toxicity is unclear. In this study we show that short-term effects of first generation NRTIs, which are rarely discussed in the literature, include inhibition of oxygen consumption, decreased ATP levels and increased ROS production. Collectively these events affect fitness and longevity of C. elegans through mitohormetic signalling events. Furthermore, we demonstrate that these effects can be normalized by addition of the anti-oxidant N-acetylcysteine (NAC), which suggests that ROS likely influence the onset and severity of adverse events upon drug exposure.

Beneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence

“…The NRTI-associated decrease in mtDNA leads to altered mitochondrial function, which in turn results in decreased ATP production, reduced mitochondrial membrane potential, increased ROS production, and modifications of the respiratory chain enzyme activity [126, 127]. Besides inhibiting mtDNA replication, NRTIs can also directly damage mitochondrial enzymes, enhancing the generation of ROS production [127]. Indeed, an increase in oxidative stress has been frequently associated with antiretroviral treatment in HIV patients [128-130].…”

Provision of combined antiretroviral therapy in HIV-positive pregnant women and the increased risk of apoptosis-related intra-uterine growth restriction

“…The myopathy was thought to be closely related to mitochondrial toxicity. This was supported by some findings in muscle biopsies of patients receiving ART therapy, such as mitochondrial defect, decreased oxidative phosphorylation (OXPHOS) activity and decreased mitochondrial DNA (mtDNA) level [21,22]. Early studies on non-nucleotide reverse transcriptase inhibitors (NRTI) drugs have shown that they exert very minimal effects on DNA polymerase alpha, but affect beta and gamma polymerase to several degrees.…”

“…In this condition, NRTIs disturb mitochondrial function via other mechanisms such as nucleoside homeostasis disturbance caused by the pharmacokinetics of NRTIs. NRTIs can also directly inhibit mito chondrial enzymes, which may increase the generation of ROS [22][23][24][25].…”

Mitochondrial DNA Parameters in Blood of Infants Receiving Lopinavir/Ritonavir or Lamivudine Prophylaxis to Prevent Breastfeeding Transmission of HIV-1

“…Indeed, Taura et al reported that LPV was the most potent inducer of ROS production in PBMCs among the PIs [ 38 ]. This production was recently shown to be an alternative mechanism of NRTI-dependent mitochondrial toxicity [ 66 ]. Even if the downstream consequences of the ROS production in this context is not clearly established, mtDNA damage might represent a side effect of LPV/r treatment.…”