HIV GLYCOPROTEIN-120 ENHANCES INTERCELLULAR-ADHESION MOLECULE-1 GENE-EXPRESSION IN GLIAL-CELLS - INVOLVEMENT OF JANUS KINASE SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION AND PROTEIN-KINASE-C SIGNALING PATHWAYS

It is well established that the two major glial cells in the central n ervous system (CNS), astrocytes and microglia, are key participants in mediating the neurologic dysfunction associated with HIV infection of the CNS. In this study, we investigated the ability of the major enve lope glycoprotein of HIV, glycoprotein 120 (gp120), to regulate interc ellular adhesion molecule-1 (ICAM-1) expression in glial cells, becaus e ICAM-1 is important in mediating immune responsiveness in the CNS, f acilitating entry of HIV-infected cells into the CNS, and promoting sy ncytia formation. Our results indicate that gp120 enhances ICAM-1 gene expression in primary rat astrocytes, primary human astrocytes, a hum an astroglioma cell line CRT, and primary rat microglia. The signal tr ansduction events involved in gp120-mediated enhancement of ICAM-1 app ear to involve activation of both protein kinase C and tyrosine kinase , because inhibitors of protein kinase C and tyrosine kinase abrogate gp120-mediated ICAM-1 expression in both astrocytes and microglia. Mor eover, gp120 induces tyrosine phosphorylation of signal transducer and activator of transcription (STAT-1 alpha) as well as the Janus kinase (JAK2) in glial cells. We also demonstrate that gp120-mediated ICAM-1 expression has functional significance, as it enhances the ability of monocytic cells to bind to gp120-stimulated human astrocytes in an IC AM-1/beta(2) integrin-dependent fashion. These results provide new ins ights into how gp120 can influence the involvement of glial cells in t he pathogenesis of AIDS dementia complex.