DYSREGULATION OF SIGNAL-TRANSDUCTION PATHWAYS AS A POTENTIAL MECHANISM OF NERVOUS-SYSTEM ALTERATIONS IN HIV-1 GP-120 TRANSGENIC MICE AND HUMANS WITH HIV-1 ENCEPHALITIS

HIV-1 associated central nervous system (CNS) disease involves neurona l damage and prominent reactive astrocytosis, the latter characterized by strong upregulation of the glial fibrillary acidic protein (GFAP) in astrocytes. Similar alterations are found in transgenic mice expres sing the HIV-1 envelope protein gp120 in the CNS. Because alterations of astrocyte functions could contribute to neuronal impairment, we com pared brains of gp120 transgenic mice and gp120-transfected C6 astrocy toma cells with controls and found that gp120 induced a prominent elev ation of steady state GFAP mRNA levels, primarily due to transcript st abilization. Increased levels of GFAP mRNA were also found in nontrans fected C6 cells exposed to recombinant gp120. Exposure of C6 cells or primary mouse astrocytes to soluble gp120 led to activation of PKC as indicated by redistribution and increase in PKC immunoreactivity at th e single cell level, gp120 effects were diminished by inhibitors of pr otein kinase C (PKC) but not inhibitors of protein kinase A. PKC activ ity was upmodulated in gp120-transfected C6 cells and in the CNS of gp 120 transgenic mice. Further, brain tissue from patients with HIV-1 en cephalitis and from gp120 transgenic mice showed increased PKC immunor eactivity. Taken together, these results indicate that gp120-induced i ncreases in PKC activity may contribute to the gliosis seen in gp120 t ransgenic mice as well as in HIV-1-infected humans and raise the quest ion of whether dysregulation of signal transduction pathways represent s a general mechanism of HIV-associated pathogenesis.