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Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection. J Virol 2016 Jan 06;90(7):3342-54

Date

01/08/2016

Pubmed ID

26739055

Pubmed Central ID

PMC4794672

DOI

10.1128/JVI.02277-15

Scopus ID

2-s2.0-84960977475   5 Citations

Abstract

UNLABELLED: 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.

IMPORTANCE: Statins are cholesterol synthesis inhibitors that are therapeutically administered to 12.5% of the U.S.

POPULATION: 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.

Author List

Lange PT, Darrah EJ, Vonderhaar EP, Mboko WP, Rekow MM, Patel SB, Sidjanin DJ, Tarakanova VL

Authors

Vera Tarakanova PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Emily Vonderhaar in the CTSI department at Medical College of Wisconsin - CTSI




MESH terms used to index this publication - Major topics in bold

Animals
Antiviral Agents
Cells, Cultured
Cholesterol
Gammaherpesvirinae
Herpesviridae Infections
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Interferon Type I
Lovastatin
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein Prenylation
Receptor, Interferon alpha-beta
Signal Transduction
Virus Latency
Virus Replication
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a