Lentivirus envelope protein exerts differential neuropathogenic effects depending on the site of expression and target cell

We investigated the neuropathogenic effects of feline immunodeficiency virus (FIV) envelope proteins in the context of both extracellular exposure and intracellular expression in feline neural cells. The envelope from the neurovirulent CSF-derived FIV V1 strain (V1-CSF) conferred infectivity to pseudotyped viruses in peripheral blood mononuclear cells (P < 0.01) in contrast to other cell types. Intracellular V1-CSF envelope expression in macrophages and microglia but not astrocytes resulted in the induction of host inflammatory genes contributing to neurotoxicity including IL-1β, TNF-α, and indolamine 2′,3′-dioxygenase (IDO) (P < 0.05) with concurrent neuronal death (P < 0.05). Upregulation of the endoplasmic reticulum stress genes was evident in brains from FIV-infected animals (P < 0.05) and in FIV-infected macrophages (P < 0.05) relative to controls. Intrastriatal implantation of an FIV envelope pseudotyped virus led to marked neuroinflammation and neuronal injury associated with neurobehavioral deficits (P < 0.01). Thus, lentivirus envelope proteins exert differential neuropathogenic effects through mechanisms that depend on the infected or exposed cell type.