title: Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection.
abstract: The cholesterol synthesis pathway is a ubiquitous cellular biosynthetic pathway that is attenuated therapeutically by statins. Importantly, type I interferon (IFN), a major antiviral mediator, also depresses the cholesterol synthesis pathway. Here we demonstrate that attenuation of cholesterol synthesis decreases gammaherpesvirus replication in primary macrophages in vitro and reactivation from peritoneal exudate cells in vivo. Specifically, the reduced availability of the intermediates required for protein prenylation was responsible for decreased gammaherpesvirus replication in statin-treated primary macrophages. We also demonstrate that statin treatment of a chronically infected host attenuates gammaherpesvirus latency in a route-of-infection-specific manner. Unexpectedly, we found that the antiviral effects of statins are counteracted by type I IFN. Our studies suggest that type I IFN signaling counteracts the antiviral nature of the subdued cholesterol synthesis pathway and offer a novel insight into the utility of statins as antiviral agents.
  
  
  OBJECTIVE
  Statins are cholesterol synthesis inhibitors that are therapeutically administered to 12.5% of the U.S.
  
  
  METHODS
  Statins attenuate the replication of diverse viruses in culture; however, this attenuation is not always obvious in an intact animal model. Further, it is not clear whether statins alter parameters of highly prevalent chronic herpesvirus infections. We show that statin treatment attenuated gammaherpesvirus replication in primary immune cells and during chronic infection of an intact host. Further, we demonstrate that type I interferon signaling counteracts the antiviral effects of statins. Considering the fact that type I interferon decreases the activity of the cholesterol synthesis pathway, it is intriguing to speculate that gammaherpesviruses have evolved to usurp the type I interferon pathway to compensate for the decreased cholesterol synthesis activity.
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Lange
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Darrah
authors.affiliation: Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Emily P
authors.initials: EP
authors.lastname: Vonderhaar
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Wadzanai P
authors.initials: WP
authors.lastname: Mboko
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Michaela M
authors.initials: MM
authors.lastname: Rekow
authors.affiliation: Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, USA.
authors.forename: Shailendra B
authors.initials: SB
authors.lastname: Patel
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Duska J
authors.initials: DJ
authors.lastname: Sidjanin
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA vera@mcw.edu.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Tarakanova
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D018142:Gammaherpesvirinae / Q000187:drug effects / Q000276:immunology*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000821:virology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007370:Interferon Type I / Q000276:immunology*; D008148:Lovastatin / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017368:Protein Prenylation; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D015398:Signal Transduction; D017735:Virus Latency / Q000187:drug effects; D014779:Virus Replication / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; D002784:Cholesterol; D008148:Lovastatin