NEUROVIRULENT SIMIAN IMMUNODEFICIENCY VIRUS REPLICATES PRODUCTIVELY IN ENDOTHELIAL-CELLS OF THE CENTRAL-NERVOUS-SYSTEM IN-VIVO AND IN-VITRO

The perivascular location of human immunodeficiency virus-infected cel ls suggests that the virus enters the central nervous system (CNS) by traversing the blood-brain barrier (BBB), In this study, the simian im munodeficiency virus (SIV) macaque model was used to determine whether SIV infects CNS endothelial cells. SIV RNA was detected in capillary endothelial cells in brain sections from animals parenterally inoculat ed with a neurovirulent strain of SIV by double immunohistochemistry a nd in situ hybridization and by reverse transcriptase in situ PCR. The se in vivo observations were extended by examining whether SIV replica ted productively in cultured macaque brain endothelial cells (MBEC). A neurovirulent strain, SIVmac239/17E-Br, replicated productively in MB EC as determined by the presence of viral cytopathic effect (syncytia) , viral DNA by PCR viral RNA by in situ hybridization, and viral antig en by immunohistochemistry: and by the production of high titers of ce ll-free virus. Virus replication was confirmed by electron microscopy. In contrast, a nonneurovirulent strain, SIVmac239, did not infect MBE C. Infection of the endothelial cells was not blocked by soluble CD4. Thus, endothelial cells may provide a CD4-independent pathway of virus entry to the CNS. In addition, damage to the BBB as a result of endot helial cell infection may provide a mechanism for amplification of vir al load in the CNS and may contribute to the CNS dysfunction that char acterizes AIDS dementia and SIV encephalitis. These data suggest that MBEC may serve a selective role in determining virus entry to the CNS.