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Journal of Virology, November 2000, p. 10153-10164, Vol. 74, No. 21
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Persistent Infection of Human Pancreatic Islets by Coxsackievirus B Is Associated with Alpha Interferon Synthesis in beta  Cells

Wassim Chehadeh,1 Julie Kerr-Conte,2 François Pattou,2 Gunar Alm,3 Jean Lefebvre,2 Pierre Wattré,1 and Didier Hober1,*

Laboratoire de Virologie, CHRU, Institut Gernez-Rieux, 59037 Lille,1 and Laboratoire de Recherche sur les Ilots de Pancréas, Faculté de Médecine, Université Lille II, 59045 Lille,2 France, and Department of Veterinary Immunology, Biomedical Center, Uppsala, Sweden3

Received 5 June 2000/Accepted 22 July 2000

The interactions of coxsackievirus B3 (CVB3), CVB4E2 (diabetogenic), and CVB4JBV (nondiabetogenic) strains with human pancreatic islets from eight adult brain-dead donors were investigated. Persistent replication of viruses in human islets was proved by detection of viral RNA by in situ hybridization, VP1 capsid protein by immunofluorescence (IF) staining, negative-strand viral RNA by reverse transcription-PCR in extracted RNA from islets, and release of infectious particles up to 30 days after infection without obvious cytolysis. By double IF staining, glucagon-containing alpha  cells and insulin-containing beta  cells were shown to be susceptible to CVB. The persistence of CVB3 and CVB4 in islet cells was associated with the chronic synthesis of alpha interferon (IFN-alpha ), as evidenced by the detection of IFN-alpha mRNA and immunoreactive IFN-alpha with antiviral activity. By double IF staining, IFN-alpha was detected in insulin-producing beta  cells only. Experiments with neutralizing anti-coxsackievirus and adenovirus receptor (CAR) antibodies provided evidence that CAR was expressed by alpha  and beta  cells and that it played a role in the infection of these cells with CVB and the consecutive IFN-alpha expression in beta  cells. The viral replication and the expression of IFN-alpha in islets were not restricted to the CVB4E2 diabetogenic strain and did not depend on the genetic background of the host. The neutralization of endogenous IFN-alpha significantly enhanced the CVB replication in islet cells and resulted in rapid destruction of islets. Thus, human beta  cells can harbor a persistent CVB infection, and CVB-induced IFN-alpha plays a role in the initiation and/or maintenance of chronic CVB infection in human islets.

* Corresponding author. Mailing address: Laboratoire de Virologie, CHRU, Institut Gernez-Rieux, 59037 Lille Cedex, France. Phone: 33 3 20 44 69 30. Fax: 33 3 20 44 52 81. E-mail: dhober{at}chru-lille.fr.

Journal of Virology, November 2000, p. 10153-10164, Vol. 74, No. 21
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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