The Roles of Genetic Polymorphisms and Human Immunodeficiency Virus Infection in Lipid Metabolism

Figure 3

Some mechanisms are proposed to explain the effects of nucleoside reverse transcriptase inhibitors (NRTIs) in the lipid profile of human immunodeficiency virus type 1- (HIV-1-) infected individuals treated with this class of antiretroviral. (1) NRTIs increase the expression and secretion of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β), that are involved in altered adipocyte function, insulin resistance, and adiponectin expression; (2) Upon entry into the cell, NRTIs are metabolized to the active triphosphorylated form and can be used as substrates by the mitochondrial DNA polymerase γ. Subsequently, they may inhibit mitochondrial DNA (mtDNA) replication and/or increase the number of mutations in mtDNA. This effect can lead to mtDNA depletion, the disruption of oxidative phosphorylation, decrease in ATP production, increase in reactive oxygen species (ROS), and, ultimately, inappropriate mitochondrial and cellular toxicity.