Control of virus reactivation arrests pulmonary herpesvirus-induced fibrosis in IFN-gamma receptor-deficient mice.
BACKGROUND
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.


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


METHODS
IFN-gamma receptor-deficient (IFN-gammaR(-/-)) mice infected intranasally with murine gamma-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 gamma-herpesvirus defective in virus reactivation from latency.


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-gammaR(-/-) mice infected with the defective reactivation mutant MHV68 v-cyclin stop. Decreased fibrosis was associated with lower levels of transforming growth factor-beta, 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.
Mora
Ana L
AL
Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Emory University, 615 Michael Street, Suite 205K, Atlanta, GA 30322, USA. amora@emory.edu
Torres-González
Edilson
E
Rojas
Mauricio
M
Xu
Jianguo
J
Ritzenthaler
Jeffrey
J
Speck
Samuel H
SH
Roman
Jesse
J
Brigham
Kenneth
K
Stecenko
Arlene
A
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D001119:Arginase / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D019084:Fluorescent Antibody Technique, Indirect; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000150:complications* / Q000473:pathology / Q000821:virology; D006909:Hydroxyproline / Q000378:metabolism; D007118:Immunoassay; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D020932:Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics; D011506:Proteins / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D017471:Receptors, Interferon / Q000172:deficiency*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018144:Rhadinovirus / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014412:Tumor Virus Infections / Q000150:complications* / Q000473:pathology / Q000821:virology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000096:biosynthesis / Q000235:genetics; D014775:Virus Activation; D001619:beta-N-Acetylhexosaminidases / Q000096:biosynthesis / Q000235:genetics; D000096743:Interferon gamma Receptor
D000956:Antigens, Viral; D001119:Arginase; D015415:Biomarkers; D016207:Cytokines; D006909:Hydroxyproline; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; D020932:Nerve Growth Factor; D011506:Proteins; D012367:RNA, Viral; D017471:Receptors, Interferon; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D014759:Viral Envelope Proteins; D001619:beta-N-Acetylhexosaminidases; D000096743:Interferon gamma Receptor; C413576:Retnla protein, mouse; C089386:glycoprotein B, murine gammaherpesvirus 68; C429541:Chil3 protein, mouse