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Published ahead of print on March 15, 2007, doi:10.1164/rccm.200610-1426OC

Am. J. Respir. Crit. Care Med., Volume 175, Number 11, June 2007, 1139-1150

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Submitted on October 5, 2006
Accepted on March 15, 2007

Control of Virus Reactivation Arrests Pulmonary Herpesvirus Induced Fibrosis in IFN{gamma}R Deficient Mice

Ana L Mora1*, Edilson Torres-Gonzalez2, Mauricio Rojas1, Jianguo Xu2, Jeffrey Ritzenthaler3, Samuel H Speck4, Jesse Roman5, Kenneth Brigham1, and Arlene Stecenko1

1 CTRL, Emory University, Atlanta, GA, USA; Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Emory University, Atlanta, GA, USA; McKelvey Lung Transplantation, Emory University, Atlanta, GA, USA, 2 CTRL, Emory University, Atlanta, GA, USA; Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Emory University, Atlanta, GA, USA, 3 Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Emory University, Atlanta, GA, USA, 4 Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA, 5 Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Emory University, Atlanta, GA, USA; Atlanta VA Medical Center, Atlanta, GA, USA

* To whom correspondence should be addressed. 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 EBV pulmonary infection and the development of IPF. Objective: To determine whether reduction of gammaherpesvirus reactivation from latency would alter progressive lung fibrogenesis in an animal model of virus-induced pulmonary fibrosis. Methods: IFN{gamma}R-/- mice infected intranasally with murine gammaherpesvirus 68 (MHV68)develop lung fibrosis that progresses for up to at least 180 days after initial infection. Virus replication during the chronic phase of infection was controlled by two methods: the administration of cidofovir, an antiviral effective at clearing lytic but not latent virus and by using a mutant gammaherpesvirus defective in virus reactivation from latency. Results: Ten percent of the asymptomatic MHV68 infected animals that received antiviral treatment beginning at day 45 post-infection had severe pulmonary fibrosis compared to 40% of the saline control infected animals. Absence of severe fibrosis was also observed in IFN{gamma}R-/- mice infected with the defective reactivation mutant MHV68 v-cyclin stop. Decreased fibrosis was associated with lower levels of TGF{beta},VEGF and markers macrophage alternative activation. When antiviral treatment was administered at day 60 in symptomatic animals, survival improved from 20 to 80% compared to untreated symptomatic animals but lung fibrosis persisted in 60% of the mice. Conclusions: MHV68 induced fibrosis is a result of virus 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




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