Mitochondrial interference by anti-HIV drugs: mechanisms beyond Pol-γ inhibition

The combined pharmacological approach to the treatment of HIV infection, known as highly active antiretroviral therapy (HAART), has dramatically reduced AIDS-related morbidity and mortality. However, its use has been associated with serious adverse reactions, of which those resulting from mitochondrial dysfunction are particularly widespread. Nucleos(t)ide-reverse transcriptase inhibitors (NRTIs) have long been considered the main source of HAART-related mitochondrial toxicity due to their ability to inhibit Pol-γ, the DNA polymerase responsible for the synthesis of mitochondrial DNA. Nevertheless, accumulating evidence points to a more complex relationship between these organelles and NRTIs. Also, alternative pathways by which other groups of anti-HIV drugs (non-nucleoside reverse transcriptase inhibitors and protease inhibitors) interfere with mitochondria have been suggested, although their implications, both pharmacological and clinical, are open to debate. This review aims to provide a comprehensive overview of the mechanisms and factors which influence the mitochondrial involvement in the toxicity of all three major classes of anti-HIV drugs.