Pathogenesis of Lipodystrophy and Lipid Abnormalities in Patients Taking Antiretroviral Therapy

HIV-associated lipodystrophy, arising as a result of long-term therapy with antiretroviral medications,is a complex syndrome characterized by changes in regional fat mass, dyslipidemia, and insulinsensitivity that, once established, is difficult to reverse. The syndrome arises largely as a result ofeffects of nucleoside reverse transcriptase inhibitors and protease inhibitors on lipid metabolism.Many of these effects have their basis at a molecular level with nucleoside reverse transcriptaseinhibitors linked to inhibition of mitochondrial RNA transcription, depletion of mitochondrial DNAand mitochondrial dysfunction and protease inhibitors linked with adipocyte toxicity through interferencewith the function of essential cellular transcription factors such as sterol regulatory elementbinding protein 1c. These molecular toxicities can affect non-adipose tissues, and together withsecondary effects on lipid and glucose metabolism of changes in body fat mass, help to contributeto the dyslipidemia and insulin resistance characteristic of this syndrome. This review will summarizewhat is known of the molecular mechanisms underlying HIV-associated lipodystrophy. A greaterunderstanding of these mechanisms is essential if effective therapeutic options are to be found.