Mechanisms and consequences of enterovirus persistence in cardiac myocytesand cells of the immune system

In humans and experimental murine models enteroviruses, and in particular c oxsackieviruses of group B (CVB), may, induce chronic myocarditis associate d with a persistent type of heart muscle infection. Persistent myocardial i nfection has been characterized by restricted viral replication and gene ex pression, which is capable of sustaining chronic inflammation. Altered repl ication and transcription of the virus, in addition to an immune response i nsufficient to recognize and clear infected cells entirely, are essential m echanisms for initiation and maintenance of persistent heart muscle infecti on. Viral cytotoxicity was found to be crucial for organ pathology both dur ing acute and persistent infection, indicating that enterovirus myocarditis is a virus-induced rather than an immune-mediated disease. Notably, resist ance to the development of persistent heart muscle infection is not linked to the H-2 haplotype of the host. In addition to persistently infected myoc ytes, detection of the replicative minus-strand RNA intermediate provided e vidence for virus replication in lymphoid cells of the spleen, predominantl y in splenic B lymphocytes, during the course of the disease. Whereas viral RNA was also detected in certain CD4(+). helper T cells and Macl(+) macrop hages, no enteroviral genomes were identified in CD8(+) T cells. Detection of infected activated B lymphocytes both in heart tissue of CVB3-infected i mmunocompetent mice and syngenic SCID mice receiving splenocytes from CVB3- infected donors support the concept that B cell traffic may contribute to m aintenance of chronic disease. Dissection of the diversity of viral and hos t-specific determinants in susceptible and resistant hosts will allow us to define the protective mechanisms that mediate resistance to the developmen t of life-threatening acute and chronic enterovirus myocarditis. (C) 1999 E lsevier Science B.V. All rights reserved.