Viruses and metabolism: alterations of glucose and glutamine metabolism mediated by human cytomegalovirus

Abstract

Recent studies of human cytomegalovirus (HCMV) infection have demonstrated that the virus significantly alters cellular metabolism, especially the utilization of glucose and glutamine. Glucose is not broken down by the tricarboxylic acid (TCA) cycle in infected cells; instead, it is used biosynthetically for fatty acid synthesis for membranes needed during the infection. In this chapter, we discuss the possibility that HCMV integrates its mechanisms for manipulating cellular signaling and stress responses to induce novel adipocyte-like differentiation in order to alter metabolism so that glucose can be used synthetically, that is, for fatty acids and lipids. This process diverts glucose from the TCA cycle and requires induction of enzymes that can convert glutamine to α-ketoglutarate to maintain the TCA cycle (anaplerosis). We discuss data proposing that the anaplerotic utilization of glutamine may be mediated, in part, by c-Myc activation, and the induction of adipocyte-like differentiation may result from the activation of the endoplasmic reticulum resident kinase PKR-like ER kinase. These alterations in metabolism during HCMV infection are comparable to those seen in many tumor cells. Indeed, the alterations in cellular signaling, stress responses, and metabolism that have been characterized could result in unexpected pathogenesis, potentially implicating HCMV as an agent or subtle cofactor in many maladies. Better understanding of HCMV's effects on cell signaling and metabolism will show how HCMV-mediated modifications of cellular processes relate to pathogenesis and will suggest novel avenues for antiviral therapy.