Role of mitochondria in HIV lipoatrophy: insight into pathogenesis and potential therapies

Abstract

Lipoatrophy is a selective loss of subcutaneous adipose tissue and a highly prevalent complication of antiretroviral therapy (ART). This form of fat wasting is associated with decreased quality of life, disincentive for adherence to antiretroviral therapy, as well as possibly an increased risk of coronary artery disease. Clinical trials have incriminated long-term ART with nucleoside analogue reverse transcriptase inhibitors (NRTIs) in general and stavudine in particular. The exact mechanism of fat wasting remains unclear, but the pathogenesis can largely be attributed to the mitochondrial toxicity of NRTIs. NRTIs are inhibitors of polymerase gamma, an enzyme which is necessary for the replication of mitochondrial DNA (mtDNA). Indeed, low amounts of mtDNA, abnormalities of mitochondrial ultrastructure, and respiratory chain dysfunction were identified in the subcutaneous fat tissue and skeletal muscle of HIV-patients under ART and linked to the use of stavudine. Switching away from the incriminated NRTI, is of proven benefit, but may not always be feasible. Supplementation with uridine should be investigated in the prevention and treatment of lipoatrophy based on its potential to competitively attenuate the mtDNA decline caused by pyrimidine NRTIs.