Mechanisms of HIV and nucleoside reverse transcriptase inhibitor injury to mitochondria.
Available evidence suggests that a number of important clinical events in individuals with HIV infection are related to mt dysfunction. Several factors may contribute to the development of these events and the tissue(s) in which the event occurs. Some individuals are likely to have important genetic predispositions for mt disease, which may be unmasked by the presence of HIV infection or the introduction of NRTI antiretrovirals. HIV infection per se is associated with reduction in mtDNA content and changes in mt morphology and function, which in some cases leads to clinical events such as myopathy or peripheral neuropathy. NRTI antiretrovirals may impact mtDNA content and function through a number of different mechanisms and have been demonstrated to be causative of a number of clinical toxicities. In in vitro and in clinical studies, newer nucleoside and nucleotides agents such as lamivudine, emtricitabine, abacavir and tenofovir appear to be much weaker inhibitors of mtDNA polymerase-gamma or other mt functions, and appear to be associated with a lower risk of events thought to be related to mt toxicity. Simple, non-invasive tests for mt function are not available at present in the clinical routine, and assays of mtDNA content in blood cells may miss key aspects of mt function, require careful sample handling and may not reflect events occurring in other tissues. There remains a need for the development of rapid, cheap and clinically applicable assays that would enable the prediction of increased likelihood of mt events.
Moyle
Graeme
G
St Stephens HIV Research, Chelsea and Westminster Hospital, London, UK. gm@moyleg.demon.co.uk
D019380:Anti-HIV Agents / Q000009:adverse effects*; D004272:DNA, Mitochondrial / Q000032:analysis; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors