Nucleoside analogues and HIV: the combined cost to mitochondria

Highly active antiretroviral therapy (HAART) has revolu- tionized human immunodeficiency virus (HIV) care in the developed world. Since the introduction of HAART the morbidity and mortality associated with HIV infection have decreased dramatically,1 but this benefit has been associated with the emergence of a diverse range of antiretroviral toxici- ties. Nucleoside reverse transcriptase inhibitors (NRTIs) are central to effective HAART, with current antiretroviral guidelines recommending the inclusion of at least two of these agents in each regimen. However, NRTIs also con- tribute significantly to the toxicities of HAART. Here we review the known mechanism of action of NRTIs, the pro- posed mechanism by which they may cause toxicities through mitochondrial damage, the evidence that HIV infection may predispose individuals to overt mitochondrial dysfunction, and potential future methods of monitoring and preventing these problems. Nucleoside analogues act as alternative substrates for DNA polymerases. Because NRTIs lack a hydroxyl group in the 3'-position (required for the addition of the next nucleo- tide onto the primer) their incorporation causes termination of the growing DNA strand. Their intended therapeutic action is to prevent the formation of HIV DNA by inhibiting HIV reverse transcriptase. However, NRTIs have the potential to cause serious cellular toxicities by interacting in a similar manner with human DNA polymerases.2 The enzymes responsible for the replication of human nuclear DNA are polymerase α and δ. Polymerase β and ε play roles in DNA repair, and polymerase γ is responsible for replication of mitochondrial DNA (mtDNA). The NRTIs currently used in the treatment of HIV infection (zidovudine, stavudine, lamivudine, didanosine, zalcitabine and abacavir) all inhibit DNA polymerases β and γ. The inhibition of poly- merase β has not been shown to be of clinical significance, but