INTRACEREBRAL HEMORRHAGES AND SYNCYTIUM FORMATION INDUCED BY ENDOTHELIAL-CELL INFECTION WITH A MURINE LEUKEMIA-VIRUS

The mechanisms of endothelial cell damage that lead to cerebral hemorr hage are not completely understood. In this study, a cloned murine ret rovirus, TR1.3, that uniformly induced stroke in neonatal BALB/c mice is described. Restriction digest mapping suggests that TR1.3 is part o f the Friend murine leukemia virus (FMuLV) family. However, unlike mic e exposed to other FMuLVs, mice infected with TR1.3 virus developed tr emors and seizures within 8 to 18 days postinoculation. This was unifo rmly followed by paralysis and death within 1 to 2 days. Postmortem ex amination of TR1.3-inoculated mice revealed edematous brain tissue wit h large areas of intracerebral hemorrhage. Histologic analysis reveale d prominent small vessel pathology including syncytium formation of en dothelial cells. Immunohistochemical analysis of frozen brain sections using double fluorescence staining demonstrated that TR1.3 virus spec ifically infected small vessel endothelial cells. Although infection o f vessel endothelial cells was detected in several organs, only brain endothelial cells displayed viral infection associated with hemorrhage . The primary determinant of TR1.3-induced neuropathogenicity was foun d to reside within a 3.0-kb fragment containing the 3' end of the pol gene, the env gene, and the U3 region of the long terminal repeat. The restricted tropism and acute pathogenicity of this cloned murine retr ovirus provide a model for studying virus-induced stroke and for eluci dating the mechanisms involved in syncytium formation by retroviruses in vivo.