Nucleoside reverse transcriptase inhibitor toxicity and mitochondrial DNA

Importance of the field: HIV/AIDS is a worldwide epidemic. While there remains no cure for the HIV-1 infection, nucleoside reverse transcriptase inhibitors (NRTIs) have helped transform the HIV-1 infection from a lethal disease into a chronic illness. Though NRTIs inhibit HIV-1 replication, they exhibit side effects in human tissues that appear to result from NRTI inhibition of human mitochondrial polymerase gamma (pol gamma). Areas covered in this review: This review discusses the current knowledge of NRTI-induced toxicity, specifically the inhibition of pol gamma and the mitochondrial toxicity from incorporation of NRTIs into mitochondrial DNA. Details are discussed about general mechanisms of NRTI toxicity and how specific tissue toxicities in mitochondria relate to clinical manifestation. What the reader will gain: A detailed knowledge of the mitochondrial toxicity resulting from NRTI-inclusive therapies and related tissue toxicities are provided. This review presents both the molecular effects of NRTI usage on mitochondrial genetic homeostasis and energy metabolism as well as the clinical manifestations associated with NRTI toxicities. Take home message: NRTIs remain a critical component of current HIV-1 treatment regimens. Future NRTIs should provide higher specificity for HIV-RT and lower incorporation by pol gamma to minimize mitochondrial toxicity. Alternatively, therapeutic interventions to prevent or alleviate mitochondrial toxicity should be addressed.