PATHOGENESIS OF CEREBRAL INFARCTION AND HEMORRHAGE-INDUCED BY A MURINE LEUKEMIA-VIRUS

BACKGROUND: Inoculation of neonatal BALB/c mice with the Friend murine leukemia virus TR1.3 uniformly induces cerebral infarctions and hemor rhages within 18 days. The primary target of TR1.3 infection are endot helial cells of capillaries and small vessels. Preliminary post-mortem histologic analysis revealed multifocal endothelial cell pathology as sociated with the presence of thrombi and extravasation of red blood c ells into the brain parenchyma, The consequences of viral infection on endothelial cell integrity and its relevance to hemorrhagic and ische mic lesions are unclear. EXPERIMENTAL DESIGN: Neonatal BALB/c mice wer e infected with TR1.3 murine leukemia virus and were monitored daily f or symptoms of tremor, seizure and paralysis. Diseased mice were kille d and the brains prepared for histopathologic analysis and electron mi croscopy studies. RESULTS: Hematoxylin and eosin-stained sections reve aled widespread areas of infarction throughout white and grey matter w ith numerous scattered thrombi. Endothelial cell pathology was widespr ead and pronounced. This included enlarged cytoplasm, intracytoplasmic clefts, separation of tight junctions, swollen mitochondria, changes to the basal lamina and in many instances the formation of syncytia. U ltrastructural studies identified numerous viral particles within the endothelial cell cytoplasm and budding from the abluminal and luminal cell surfaces. CONCLUSIONS: These data confirm that TR1.3 virus replic ates within endothelial cells and provides the first direct evidence o f retrovirus-induced endothelial cell pathology. These results suggest that hemorrhage may be a direct consequence of this endothelial cell pathology, and that endothelial cell damage initiates the formation of thrombi and vessel occlusion that results in multiple cerebral infarc tions.