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Interferon Regulates Acute and Latent Murine Cytomegalovirus Infection and Chronic Disease of the Great Vessels

From the Center for Immunology, Departments of Pathology and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110

To define immune mechanisms that regulate chronic and latent herpesvirus infection, we analyzed the role of interferon (IFN-) during murine cytomegalovirus (MCMV) infection. Lethality studies demonstrated a net protective role for IFN-, independent of IFN-/β, during acute MCMV infection. Mice lacking the IFN- receptor (IFN-R^–/–) developed and maintained striking chronic aortic inflammation. Arteritis was associated with inclusion bodies and MCMV antigen in the aortic media. To understand how lack of IFN- responses could lead to chronic vascular disease, we evaluated the role of IFN- in MCMV latency. MCMV-infected IFN-R^–/– mice shed preformed infectious MCMV in spleen, peritoneal exudate cells, and salivary gland for up to 6 mo after infection, whereas the majority of congenic control animals cleared chronic productive infection. However, the IFN-R was not required for establishment of latency. Using an in vitro explant reactivation model, we showed that IFN- reversibly inhibited MCMV reactivation from latency. This was at least partly explained by IFN-– mediated blockade of growth of low levels of MCMV in tissue explants. These in vivo and in vitro data suggest that IFN- regulation of reactivation from latency contributes to control of chronic vascular disease caused by MCMV. These studies are the first to demonstrate that a component of the immune system (IFN-) is necessary to regulate MCMV-associated elastic arteritis and latency in vivo and reactivation of a herpesvirus from latency in vitro. This provides a new model for analysis of the interrelationships among herpesvirus latency, the immune system, and chronic disease of the great vessels.

Key Words: interferon • latency • reactivation • cytomegalovirus • vasculitis

H.W. Virgin IV was supported by grant AI-39616 from the National Institute of Allergy and Infectious Diseases and the Monsanto-Searle Biomedical Agreement. A.J. Dal Canto was supported by National Institutes of Health (NIH) training grant 5T32 AI-07172 and NIH grant GM-07200. R.M. Presti was supported by NIH grant GM-07200. J.L. Pollock was supported by NIH training grant 5T32 AI-07163 and by the Lucille P. Markey Pathway at Washington University School of Medicine.

Rachel M. Presti and Jessica L. Pollock contributed equally to the work presented in this paper.

Abbreviations used: HV68, murine -herpesvirus 68; HCMV, human cytomegalovirus; HSV, herpes simplex virus; MCMV, murine cytomegalovirus; MEF, murine embryonic fibroblasts; PEC, peritoneal exudate cell; sgMCMV, salivary gland MCMV; tcMCMV, tissue culture–passaged MCMV.

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