PATHOGENESIS OF OVINE LENTIVIRAL ENCEPHALITIS - DERIVATION OF A NEUROVIRULENT STRAIN BY IN-VIVO PASSAGE

The lentiviruses of sheep replicate almost exclusively in macrophages and cause chronic interstitial pneumonia, arthritis, and mastitis, but only rarely encephalitis. This study was undertaken to determine whet her a non-neurovirulent field strain of ovine lentivirus isolated from joint fluid that replicated productively in lung and joint macrophage s could be adapted to enter and replicate in the brain and cause encep halitis. The field isolate was passed seven times sequentially by intr acerebral inoculation of sheep. The neuroadapted strain of virus cause d severe encephalitis typical of visna in four of four sheep inoculate d intracerebrally. The virus replicated to high titers in the brains o f these animals and in cultured microglia, The inflammatory response i n the brain was characterized by intense infiltrates of macrophages an d CD8(+) and CD4(+) T cells. Many of the perivascular macrophages demo nstrated TNF-alpha expression and there was upregulation of MHC Class II antigen expression on both inflammatory cells and endothelium. Inoc ulation of this neuroadapted virus into the bone marrow of three anima ls resulted in persistent infection and cell-associated viremia, but n ot encephalitis, Virus was not detected in brains from these animals, indicating that the virus was not neuroinvasive, These data suggest th at neuroinvasiveness and neurovirulence are separate pathogenic determ inants, both of which are required for the development of encephalitis during natural infection.