Intracerebral Hemorrhages andSyncytium Formation Induced byEndothelial CellInfection withaMurineLeukemia Virus

Themechanisms ofendothelial cell damagethat lead tocerebral hemorrhage arenotcompletely understood. Inthis study, acloned murineretrovirus, TR1.3, thatuniformly induced stroke inneonatal BALB/cmiceis described. Restriction digest mapping suggests thatTR1.3ispartoftheFriendmurineleukemia virus (FMuLV)family. However, unlike miceexposed toother FMuLVs,miceinfected withTR1.3virus developed tremors andseizures within 8to18dayspostinoculation. Thiswasuniformly followed byparalysis anddeath within 1to2days. Postmortem examination ofTR1.3-inoculated micerevealed edematous brain tissue with large areasofintracerebral hemorrhage. Histologic analysis revealed prominent smallvessel pathology including syncytium formation ofendothelial cells. Immunohistochemical analysis offrozen brainsections using double fluorescence staining demonstrated that TR1.3virus specifically infected small vessel endothelial cells. Although infection ofvessel endothelial cells wasdetected inseveral organs, only brainendothelial cells displayed viral infection associated withhemorrhage. Theprimary determinant ofTR1.3-induced neuropathogenicity wasfound toreside within a3.0-kb fragment containing the3'endofthepolgene, theenvgene, and theU3region ofthelong terminal repeat. Therestricted tropism andacute pathogenicity ofthis cloned murine retrovirus provide amodelforstudying virus-induced stroke andforelucidating themechanisms involved in syncytium formation byretroviruses invivo.