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Control of Virus Reactivation Arrests Pulmonary Herpesvirus-induced Fibrosis in IFN- Receptor–deficient Mice

¹ Center for Translational Research of the Lung, ² Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, ³ McKelvey Lung Transplantation Center, and ⁴ Department of Microbiology and Immunology, Emory University, Atlanta, Georgia; ⁵ Atlanta VA Medical Center, Atlanta, Georgia; and ⁶ Division of Pediatric Pulmonology, Allergy, Cystic Fibrosis, and Sleep Medicine, Department of Pediatrics, Emory University, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to Ana L. Mora, M.D., Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Emory University, 615 Michael Street, Suite 205K, Atlanta, GA 30322. E-mail: amora{at}emory.edu

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disorder of unknown cause. Several studies suggest an association between Epstein-Barr virus pulmonary infection and the development of IPF.

Objectives: To determine whether reduction of -herpesvirus reactivation from latency would alter progressive lung fibrogenesis in an animal model of virus-induced pulmonary fibrosis.

Methods: IFN- receptor–deficient (IFN-R^–/–) mice infected intranasally with murine -herpesvirus 68 (MHV68) develop lung fibrosis that progresses for up to at least 180 days after initial infection. Viral replication during the chronic phase of infection was controlled by two methods: the administration of cidofovir, an antiviral drug effective at clearing lytic but not latent virus, and by using a mutant -herpesvirus defective in virus reactivation from latency.

Measurements and Main Results: Ten percent of the asymptomatic MHV68-infected animals that received antiviral treatment beginning on Day 45 postinfection had severe pulmonary fibrosis compared with 40% of the control saline-treated animals. Absence of severe fibrosis was also observed in IFN-R^–/– mice infected with the defective reactivation mutant MHV68 v-cyclin stop. Decreased fibrosis was associated with lower levels of transforming growth factor-, vascular endothelial growth factor, and markers of macrophage alternative activation. When antiviral treatment was administered on Day 60 in symptomatic animals, survival improved from 20 to 80% compared with untreated symptomatic animals, but lung fibrosis persisted in 60% of the mice.

Conclusions: MHV68-induced fibrosis is a result of viral lytic replication during chronic lung herpesvirus infection in mice. We speculate that antiviral therapy might help to control lung fibrosis in humans with IPF and associated herpesvirus infection.

Key Words: lung • fibrosis • herpesvirus • antiviral

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease without a proven treatment. Several studies suggest an association between herpesvirus infection in the lung and IPF. What This Study Adds to the Field Using a murine herpesvirus–induced lung fibrosis model, we show that antiviral therapy controls virus replication during chronic infection and prevents lung fibrosis. Patients with IPF with associated herpesvirus infection might benefit from antiviral therapy.

 

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