INDUCTION OF CYTOKINES BY HIV-1 AND ITS GP120 PROTEIN IN HUMAN PERIPHERAL-BLOOD MONOCYTE MACROPHAGES AND MODULATION OF CYTOKINE RESPONSE DURING DIFFERENTIATION/

We previously reported that in vitro culture of human peripheral blood monocytes resulted in a time-dependent differentiation into macrophag es and in an enhanced capacity for producing certain cytokines [i.e., tumor necrosis factor alpha, interleukin-6 (IL-6), and interferon-beta (IFN-beta)] in response to bacterial lipopolysaccharide (LPS), HIV-1 infection or gp120 treatment of monocyte/macrophages resulted in the i nduction of low levels of IFN-beta, which were very effective in restr icting viral replication in 7-day cultured macrophages but not in fres hly isolated cells, This enhanced response of macrophages was due to a higher sensitivity of these cells to the antiviral effect of IFN-beta , Consistent with this finding, 7-day cultured macrophages exhibited h igher levels of type I IFN receptors than 1-day cultured monocytes, Tr eatment of monocyte/macrophages with gp120 also caused a marked increa se in IL-10 secretion, regardless of the differentiation state. No IL- 12 secretion was detected in monocyte/macrophage cultures treated with gp120 alone, However, consistent IL-12 secretion wits found in 7-day cultured macrophages primed with IFN-beta and subsequently stimulated with gp120, Macrophages responded more efficiently than monocytes to t he priming effect of IFN-beta for IL-12 production, This was consisten t with a stronger antiviral response against vesicular stomatitis viru s by these cells as well as with a higher expression of IFN-beta recep tors, The finding that the acquisition of the macrophage phenotype is associated with an increased capacity to respond to environmental sign als (such as type I and type II IFNs) underlines the importance of the differentiation process for the selection of a certain repertoire of responses that may allow these cells to have important functions in vi vo.