PROINFLAMMATORY CYTOKINES INHIBIT HIV-1(SF162) EXPRESSION IN ACUTELY INFECTED HUMAN BRAIN-CELL CULTURES

An understanding of how viral replication in glial cells responds to p roinflammatory cytokines is important in delineating HIV-1 neuropathog enesis. Because no information is available in the literature regardin g the regulatory effects of exogenous cytokines on acute HIV-1 replica tion in human brain cells, we studied the impact of cytokine treatment on viral p24 Ag expression. Eased upon reports using mononuclear phag ocytes derived from somatic sources, we hypothesized that TNF-alpha, I L-1 beta, and IL-6 would up-regulate the expression of HIV-1(SF162) (a monocytotropic strain) in purified microglial cells and in mixed brai n cell cultures. This hypothesis was not supported. In fact, a contrar y, unexpected result was obtained; whereas in purified microglial cult ures TNF-alpha displayed a mild stimulatory effect on HIV-1 expression (15% increase in p24 Ag production compared with control cultures), s urprisingly, IL-1 beta and IL-6 were highly suppressive (91 and 83% in hibition of HIV expression, respectively). In contrast to the findings in microglial cell cultures, TNF-alpha profoundly suppressed (84%) HI V-1 expression in mixed brain cell cultures, as did IL-1 beta (82%), a nd IL-6 was moderately suppressive (55% inhibition). In an attempt to identify factors responsible for the differential effects of TNF-alpha in the two brain cell infection models, it was found that compared wi th microglial cell cultures, TNF-alpha treatment of mixed brain cell c ultures released significantly greater amounts of RANTES (regulated up on activation, normal T cell expressed and secreted) and macrophage in flammatory protein-let, beta-chemokines that have been suggested to ha ve anti-HIV-1 effects. Thus, these data suggest that proinflammatory c ytokines possess anti-HIV-1 activity in the central nervous system.