Viruses are obligate intracellular pathogens that require a host cell to multiply and expand the infection. They have evolved to reprogram key pathways in the host to obtain the metabolic intermediates (nucleotides, fatty acids or amino acids) required for the biosynthesis of macromolecules. These changes shift the cell toward an anabolic state which resembles those that occur in cancer cells. One of the most notorious is the Warburg effect in which cells preferentially utilize glycolysis instead of oxidative phosphorylation (OxPhos) despite the presence of oxygen. Thus, both, cancer and viral-infected cells display an enhanced glucose uptake and lactate secretion. Glycolytic intermediates and TCA cycle metabolites are used as carbon skeletons for anabolic processes while the pentose phosphate pathway (PPP) provides NADPH. The PPP also provides intermediates for the synthesis of the nucleotides required for DNA/RNA synthesis. Additionally, like neoplastic cells, virus-infected cells display a high dependence for glutamine and increase its cellular uptake and the glutaminase activity. Glutamine is converted to a-ketoglutarate to replenish a TCA cycle that loses malate, oxaloacetate and citrate to provide biosynthetic intermediates.
Viruses use a variety of strategies to reprogram host metabolism. This is achieved through key signaling pathways that are at the hub of the control of metabolism. The phosphoinositide 3-kinase (PI3K) - AKT pathway and its target mTOR are probably two of the most important pathway that stimulates anabolism in tumor cells. A number of viruses have already been shown to activate PI3K to support viral replication. The hypoxia-inducible factor (HIF) is another key player in the metabolic adaptations and, particularly, in cancer. HIF-1a induces pyruvate dehydrogenase kinase (PDK) which prevents the mitochondrial oxidation of pyruvate by inactivating pyruvate dehydrogenase (PDH), the enzyme that converts pyruvate to acetyl-CoA. HIF-1a also increases glucose uptake (upregulation of GLUT transporters) and facilitates the conversion of pyruvate into lactate by stimulating the expression of lactate dehydrogenase (LDH). These two concerted effects, PDH inhibition and LDH overexpression, shift the energy metabolism from oxidative phosphorylation to glycolysis. Viruses are known to use different mechanisms to activate HIF-1a its target IL-1b, to sustain their replication.
Our research project aims to identify drugs that revert the viral-induced metabolic reprogramming in their host cells. Special emphasis is place on the repositioning of existing clinical drugs as antiviral agents.