Murine gammaherpesvirus-68 infection of and persistence in the central nervous system.

ABSTRACT

Murine gammaherpesvirus-68 (MHV-68) was originally isolated from a bank vole by passage through mouse brain. Given its ability to replicate in mouse brain and its subsequent reisolation from trigeminal ganglia, it was originally considered to be an alphaherpesvirus. Molecular studies have now firmly established MHV-68 to be a gammaherpesvirus. Other gammaherpesviruses have been suggested to cause and in some cases shown to cause neurological disease. Given the isolation history of MHV-68, we have studied the ability of this virus to gain access to, to replicate in and to persist in the mouse CNS. Following intranasal inoculation the virus was not generally neuroinvasive. However, in mice with a deletion of the type-I interferon receptor gene, peripheral virus titres are higher and perivascular CNS infection was observed. There was no evidence of virus spread via olfactory routes. Direct intracerebral inoculation of virus was fatal with widespread infection and destruction predominantly of meningeal and ependymal cells. Hippocampal pyramidal neurons, oligodendrocytes, Bergmann glia cells in the cerebellar cortex and neural progenitor cells in the rostral migratory stream were also infected. A similar infection was observed in younger mice. CNS infection following virus reactivation was investigated by implantation of infected glial cells. Implantation into a brain ventricle led to widespread fatal infection, principally involving ependymal and meningeal cells. Implantation into the striatum resulted in a predominantly neuronal infection. Implantation of cells into mice transiently treated with the antiviral thionucleoside analogue 2'-deoxy-5-ethyl-beta-4'-thiouridine resulted in survival with detection of virus-infected cells in the brain 1 year later.