Figure 7

Schematic overview of the network of enriched pathways related to HIV disease progression. HIV accessory proteins and side effects of therapy could lead to the impaired activity of electron transport chain complex I, which results in mitochondrial dysfunction. As a compensatory effect, OXPHOS pathway (electron transport chain and ATP synthase) is up-regulated as indicated by the red arrow. Along with the OXPHOS pathway, the TCA cycle supplying NADH to OXPHOS, and a wide range of metabolic pathways (carbohydrate, fatty acid, protein, and amino acid metabolism pathways) furnishing substrates to the TCA cycle are coordinately up-regulated. In addition, mitochondrial dysfunction leads to cell apoptosis mediated by the activation of mitochondrial membrane pore-forming proteins, such as BAX and BAD. Pores generated in the mitochondrial membranes allow the release of the pro-apoptotic proteins cytochrome c, which binds to APAF and hence activates CASP9 leading to the caspase cascade resulting in apoptosis. G2 arrest and DNA damage signaling could also activate BAX leading to mitochondria-mediated apoptosis. On the other hand, AKT could prevent apoptosis by either inhibiting BAD or CASP9 activation or preventing FOXO factors from relocating to the nucleus.