Mitochondrial Dysfunction and Nucleoside Reverse Transcriptase Inhibitor Therapy

New, more effective antiretroviral therapeutic agents (1 and promise from HIV vaccine studies (2) have not yet prevented the AIDS epidemic’s global spread. Nucleoside reverse transcriptase inhibitors (NRTIs), in combinations termed highly active antiretroviral therapy (HAART), are cornerstones of AIDS therapy in the developed world. Biochemical, cell biological, and clinical features intertwine to amplify the DNA polymerase-γ hypothesis (3) into a mitochondrial dysfunction hypothesis (4) that focuses on the effects on mitochondrial DNA (mtDNA) replication and intramitochondrial and intracellular processing of NRTIs (5) . During the past decade or longer, it has become increasingly reasonable to link organelle (i.e., mitochondrial) toxicity to NRTI therapy and to consider that the mechanisms operative in the pathogenesis of NRTI toxicity are interrelated with the mitochondria. Early observations were based on in vitro experiments (6) , animal experiments confirmed those findings in vivo (7–9) , and clinical correlations were found in AIDS patients (4,10)