Human cytomegalovirus (HCMV), a herpes virus, is a ubiquitous human pathogen that infects over 60% of the adult population. It is a major cause of birth defects, a life-threatening opportunistic agent in immuno-suppressed people, and a possible cofactor in certain cancers. Using liquid chromatography-mass spectrometry-based metabolomics together with isotope tracers, we have discovered that HCMV profoundly up-regulates many host cell metabolic pathways, including glycolysis, the TCA cycle, and lipid biosynthesis. These metabolic changes are evocative of those occurring in cancer. We have compared HCMV and herpes simplex virus-1, and found that the metabolic effects of the latter virus, while also strong, are quite different from those of HCMV. This indicates that different related viruses encode distinct programs for host cell metabolic hijacking. Importantly, we have used siRNAs and drugs to show that successful HCMV replication depends on multiple metabolic enzymes. Inhibitors of acetyl-CoA carboxylase, elongases (ELOVLs) and acyl-CoA synthetases block the production of HCMV progeny. These enzymes are needed to produce very long chain fatty acids, and we have recently discovered that the envelope of HCMV virions is enriched about 10-fold in such fatty acid tails. Thus, HCMV's life cycle requires synthesis of specific lipid species. As inhibitors of lipid biosynthetic enzymes can be safe and well tolerated, the sensitivity of HCMV to host cell lipid production may reflect a therapeutically important metabolic vulnerability. The major metabolic effects of HCMV raise critical fundamental questions: How does HCMV alter host cell metabolism? Which specific lipids does HCMV require? How do these contribute to viral replication? We propose to address these questions using a multidisciplinary combination of virology, biochemistry and systems biology. Specifically, we will: (i) assess the program of lipid metabolic changes induced by HCMV and determine how drugs that block specific metabolic enzymes needed by the virus alter this program;(ii) investigate the mechanism by which HCMV alters metabolism;and (iii) determine how the metabolic changes support HCMV replication. These studies address an important and understudied area of HCMV biology, they will advance fundamental understanding of metabolic regulation, and they will lay the foundation for the discovery of novel anti-virals.

Public Health Relevance

Human cytomegalovirus (HCMV) is a major cause of birth defects, a life-threatening opportunistic agent in immuno suppressed people, and a possible cofactor in certain cancers. The host metabolic environment is dramatically altered during infection with HCMV. The virus induces many metabolic pathways, with several lipid biosynthetic pathways essential for the production of virus progeny. We will explore the means by which the virus turns on these pathways, and the ways in which they contribute to viral replication. Our results will provide new insights into mechanisms underlying HCMV infection, information essential to our ultimate ability to develop new therapies and control infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Virology - A Study Section (VIRA)
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Beisel, Christopher E
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Princeton University
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Liu, Ling; Shah, Supriya; Fan, Jing et al. (2016) Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage. Nat Chem Biol 12:345-52
Su, Xiaoyang; Wellen, Kathryn E; Rabinowitz, Joshua D (2016) Metabolic control of methylation and acetylation. Curr Opin Chem Biol 30:52-60
Purdy, John G; Shenk, Thomas; Rabinowitz, Joshua D (2015) Fatty acid elongase 7 catalyzes lipidome remodeling essential for human cytomegalovirus replication. Cell Rep 10:1375-85
Stincone, Anna; Prigione, Alessandro; Cramer, Thorsten et al. (2015) The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc 90:927-63
Xu, Yi-Fan; Lu, Wenyun; Rabinowitz, Joshua D (2015) Avoiding misannotation of in-source fragmentation products as cellular metabolites in liquid chromatography-mass spectrometry-based metabolomics. Anal Chem 87:2273-81
Mathew, Robin; Khor, Sinan; Hackett, Sean R et al. (2014) Functional role of autophagy-mediated proteome remodeling in cell survival signaling and innate immunity. Mol Cell 55:916-930
Hwang, Jesse; Purdy, John G; Wu, Kai et al. (2014) Estrogen-related receptor ? is required for efficient human cytomegalovirus replication. Proc Natl Acad Sci U S A 111:E5706-15
Fan, Jing; Ye, Jiangbin; Kamphorst, Jurre J et al. (2014) Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510:298-302
Koyuncu, Emre; Budayeva, Hanna G; Miteva, Yana V et al. (2014) Sirtuins are evolutionarily conserved viral restriction factors. MBio 5:
Koyuncu, Emre; Purdy, John G; Rabinowitz, Joshua D et al. (2013) Saturated very long chain fatty acids are required for the production of infectious human cytomegalovirus progeny. PLoS Pathog 9:e1003333

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