Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity

Abstract

The introduction of highly active antiretroviral therapy (HAART) for treatment of human immunodeficiency virus (HIV) infection has led to substantial reduction in morbidity and near-complete suppression of HIV-1 replication. But since HAART is unlikely to eradicate HIV-1, antiviral therapy may be required a lifelong, leading to an increase in attention on the long-term safety of HAART. A major toxicity of HAART is the mitochondrial toxicity. Mitochondrial toxicity becomes apparent particularly over the medium-term to long-term therapy and is attributed to treatment with nucleoside reverse transcriptase inhibitors (NRTIs), leading to a wide range of severe adverse events in HIV-infected patients. These include lactic acidosis, hepatic steatosis, neuropathy, (cardio-) myopathy, pancreatitis, and probably lipodystrophy. Furthermore, lactic acidosis and encephalopathy have been reported in children exposed in-utero and/or postnatally to NRTIs. Mitochondrial toxicity could pose a major threat to long-term success of HIV-therapy, and is of great concern for children exposed in-utero and/or postnatally to NRTIs. Therefore, investigation of mitochondrial toxicity of new compounds or new combinations is of growing interest for the clinical application of antiretroviral agents. However, at present no standardized and validated screening model system exists for the investigation of NRTI-induced mitochondrial toxicity. There is a need for the generation of a relevant in vitro assay system that can assess the mitochondrial toxicity in early preclinical development. This paper gives an overview of cell culture models currently used for the investigation of NRTI-induced mitochondrial toxicity and discusses the relevance and suitability of these models for prediction of clinical toxicity.