title: Divergent effects of human cytomegalovirus and herpes simplex virus-1 on cellular metabolism.
abstract: Viruses rely on the metabolic network of the host cell to provide energy and macromolecular precursors to fuel viral replication. Here we used mass spectrometry to examine the impact of two related herpesviruses, human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1), on the metabolism of fibroblast and epithelial host cells. Each virus triggered strong metabolic changes that were conserved across different host cell types. The metabolic effects of the two viruses were, however, largely distinct. HCMV but not HSV-1 increased glycolytic flux. HCMV profoundly increased TCA compound levels and flow of two carbon units required for TCA cycle turning and fatty acid synthesis. HSV-1 increased anapleurotic influx to the TCA cycle through pyruvate carboxylase, feeding pyrimidine biosynthesis. Thus, these two related herpesviruses drive diverse host cells to execute distinct, virus-specific metabolic programs. Current drugs target nucleotide metabolism for treatment of both viruses. Although our results confirm that this is a robust target for HSV-1, therapeutic interventions at other points in metabolism might prove more effective for treatment of HCMV.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Livia
authors.initials: L
authors.lastname: Vastag
authors.forename: Emre
authors.initials: E
authors.lastname: Koyuncu
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Grady
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Shenk
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002952:Citric Acid Cycle; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000188:drug therapy / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D006019:Glycolysis; D006561:Herpes Simplex / Q000188:drug therapy / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D011743:Pyrimidines / Q000096:biosynthesis; D011766:Pyruvate Carboxylase / Q000378:metabolism; D014709:Vero Cells; D014779:Virus Replication / Q000502:physiology*
chemical_list: D011743:Pyrimidines; D011766:Pyruvate Carboxylase; C030986:pyrimidine