Both subgroup strains of TMEV infect mainly neurons during the acute stage of infection [
1‐
4]. It is of interest that DA viral antigen and RNA that are present in neurons during the acute stage of infection disappear from neurons in the chronic demyelinating stage, presumably because these cells are cleared, perhaps by apoptosis. The cellular localization of DA viral antigen and RNA in the chronic demyelinating stage is somewhat controversial. There are two proposals: viral persistence in oligodendrocytes and/or viral persistence in macrophages. Immunoelectron microscopic study have shown viral antigen in oligodendrocytes at 45 days p.i. or later. Based on this, Rodriguez and coworkers proposed that a "gdying-back" process might occur in virus-infected oligodendrocytes [
21,
22], resulting in demyelination. In nude mice, demyelination occurs without evidence of myelin stripping by macrophages, suggesting that the demyelination occurs secondary to a lytic infection of oligodendrocytes [
23]. Also, in nude mice, electron microscopic studies have demonstrated paracrystalline arrays of picornavirus in degenerating glial cells, many of which were identified as oligodendrocytes. A lytic infection of oligodendrocytes has been proposed as a cause of the demyelination [
24]. On the other hand, a number of studies have found that the virus persists in macrophages. Using ultrastructural immnohistochemical techniques, researchers have observed viral inclusions in macrophages in and around demyelinating lesions [
25]. Two-color immunofluorescent staining has shown that viral antigen is predominantly within macrophages infiltrating demyelinating lesions [
26]. Infectious virus can be recovered from infiltrating mononuclear cells isolated directly from the central nervous system (CNS) [
27]. Cultured primary brain macrophages can be efficiently infected with the DA strain without the induction of a significant cytopathic effect [
28]. The importance of macrophages in late demyelinating disease is further emphasized by the observation that depletion of blood-borne macrophages by dichloromethylene diphosphonate prevents virus persistence in mice infected with the DA strain [
29]. From these data, it appears likely that macrophages are the major cells containing persistent viral genome. Therefore, the mechanism by which DA survives in macrophages may clarify DA persistence.