Interferon regulatory factor 1 restricts gammaherpesvirus replication in primary immune cells

• Published in: Journal of virology Vol. 88; no. 12; pp. 6993 - 7004
• Main Authors: Mboko, Wadzanai P, Mounce, Bryan C, Emmer, Joseph, Darrah, Eric, Patel, Shailendra B, Tarakanova, Vera L
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-06-2014
• Subjects: Animals; Cells, Cultured; Gammaherpesvirus; Herpesviridae Infections - immunology; Herpesviridae Infections - veterinary; Herpesviridae Infections - virology; Interferon Regulatory Factor-1 - genetics; Interferon Regulatory Factor-1 - immunology; Interferon Type I - immunology; Macrophages - immunology; Macrophages - virology; Mice; Mice, Inbred C57BL; Mice, Knockout; Rhadinovirus - genetics; Rhadinovirus - physiology; Rodent Diseases - immunology; Rodent Diseases - virology; Virus Replication; Virus-Cell Interactions
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/jvi.00638-14

Gammaherpesviruses are ubiquitous pathogens that establish a lifelong infection and are associated with cancer. In spite of the high seroprevalence of infection, the risk factors that predispose the host toward gammaherpesvirus-induced malignancies are still poorly understood. Interferon (IFN) regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. On the basis of its biology, IRF-1 represents a plausible host factor to attenuate gammaherpesvirus infection and tumorigenesis. In this study, we show that IRF-1 restricts gammaherpesvirus replication in primary macrophages, a physiologically relevant immune cell type. In spite of the known role of IRF-1 in stimulating type I IFN expression, induction of a global type I IFN response was similar in IRF-1-deficient and -proficient macrophages during gammaherpesvirus infection. However, IRF-1 was required for optimal expression of cholesterol-25-hydroxylase, a host enzyme that restricted gammaherpesvirus replication in primary macrophages and contributed to the antiviral effects of IRF-1. In summary, the current study provides an insight into the mechanism by which IRF-1 attenuates gammaherpesvirus replication in primary immune cells, a mechanism that is likely to contribute to the antiviral effects of IRF-1 in other virus systems.
Interferon regulatory factor 1 (IRF-1) is a transcription factor that regulates innate and adaptive immune responses and functions as a tumor suppressor. IRF-1 restricts the replication of diverse viruses; however, the mechanisms responsible for the antiviral effects of IRF-1 are still poorly understood. Gammaherpesviruses are ubiquitous pathogens that are associated with the induction of several malignancies. Here we show that IRF-1 expression attenuates gammaherpesvirus replication in primary macrophages, in part by increasing expression of cholesterol-25-hydroxylase (CH25H). CH25H and its product, 25-hydroxycholesterol, restrict replication of diverse virus families. Thus, our findings offer an insight into the mechanism by which IRF-1 attenuates the replication of gammaherpesviruses, a mechanism that is likely to be applicable to other virus systems.