Persistent infection of human pancreatic islets by coxsackievirus B is associated with alpha interferon synthesis in beta cells

The interactions of coxsackievirus B3 (CVB3), CVB4E2 (diabetogenic), and CV B4JBV (nondiabetogenic) strains with human pancreatic islets from eight adu lt brain-dead donors were investigated. Persistent replication of viruses i n human islets was proved by detection of viral RNA by in situ hybridizatio n, VP1 capsid protein by immunofluorescence (IF) staining, negative-strand viral RNA by reverse transcription-PCR in extracted RNA from islets, and re lease of infectious particles up to 30 days after infection without obvious cytolysis. By double IF staining, glucagon-containing or 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 st aining, IFN-alpha was detected in insulin-producing beta cells only. Experi ments with neutralizing anti-coxsackievirus and adenovirus receptor (CAR) a ntibodies 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 t he expression of IFN-alpha in islets were not restricted to the CVB4E2 diab etogenic strain and did not depend on the genetic background of the host. T he neutralization of endogenous IFN-alpha significantly enhanced the CVB re plication in islet cells and resulted in rapid destruction of islets. Thus, human beta cells can harbor a persistent CVB infection, and CVB-induced IF N-alpha plays a role in the initiation and/or maintenance of chronic CVB in fection in human islets.