Possible ways nucleoside analogues can affect mitochondrial DNA content and gene expression during HIV therapy

In recent years, research into nucleoside reverse transcriptase inhibitor (NRTI)-related mitochondrial (mt) toxicity in HIV therapy has led to conflicting results and many unanswered questions regarding the molecular mechanisms that lead to such toxicity. From the early hypothesis that inhibition of the human mt polymerase gamma by NRTls was responsible for the drugs' mt toxicity, an increasingly complex picture is emerging that probably involves multiple mt pathways. Results have been presented suggesting that NRTIs affect not only mtDNA but also mtRNA, nucleotide phosphorylation and the mt respiratory chain. Based on the current level of knowledge, this overview addresses some of the potential mechanisms through which NRTIs could affect mitochondria and ultimately cause the toxicity symptoms observed in HIV patients receiving NRTI-containing antiretroviral therapy.