INDUCTION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION IN HUMANGLIAL-CELLS AFTER PROINFLAMMATORY CYTOKINES STIMULATION - EFFECT OF IFN-GAMMA, IL1-BETA, AND TNF-ALPHA ON DIFFERENTIATION AND CHEMOKINE PRODUCTION IN GLIAL-CELLS

Although evidence for human immunodeficiency virus 1 (HIV-1) presence in the central nervous system (CNS) of infected patients is well estab lished, the intensity of viral replication within the brain is not usu ally known. In vitro, human embryonic microglial cells internalized HI V-1 through a CD4-dependent pathway but were not per missive to viral replication. We observed that HIV replication was induced when CNS cel l cultures were stimulated for 14 days by a combination of proinflamma tory cytokines including IFN gamma, IL1 beta, and TNF alpha. After lon g-term cytokine stimulation, morphologically differentiated glial cell s appeared, in which HIV-1 tat antigen was detected after infection. T hus, variations in the stage of maturation/activation of CNS cells und er inflammatory conditions probably play a major role in facilitating massive production of HIV-1. We then studied the effect of prolonged c ytokine stimulation on the secretion of inflammatory mediators by glia l cells. An early increased secretion of prostaglandin F2 alpha and ch emokines (RANTES much greater than MIP-1 alpha much greater than MIP-1 beta) was observed, due to both microglia and astrocytes. In contrast to persistent PGF2 alpha production, an extinction of RANTES and MIP- 1 beta but not of MIP-1 alpha secretion occurred during the 14 days of stimulation and was inversely correlated with the ability of glial ce lls to replicate HIV-1. The study of the secretory factors produced in response to a persistent inflammation could provide a better understa nding of the modulation of HIV replication in glial cells. (C) 1998 Wi ley-Liss, Inc.