Cocaine has been demonstrated to have a number of different effects on immune cell functions. We have reported alterations of cellular functions by macrophages (M) exposed to cocaine in vitro, including the inhibition of mouse hepatitis virus replication. Here, we present evidence that cocaine stimulates the secretion of an antiviral product that is neutralized by anti-interferon (anti-IFN). A dose-dependent increase in the secretion of IFN by both M and L929 cells incubated with cocaine, with a concomitant decrease in virus replication, is also reported. The increase in IFN secretion was most pronounced when cells were cultured in the presence of the IFN inducer poly(I⅐C). The effect of cocaine on IFN production was found to be primarily at the transcript level in both M and L929 cells. These findings further support our previous research demonstrating an antiviral activity of cocaine in vitro. The relevance of this activity to viral infections in general remains to be determined.Cocaine has been reported to exhibit a variety of immunomodulatory effects on different immune functions (30). Previous reports by us and others have demonstrated that macrophages (M) exposed to cocaine in vitro displayed increased phagocytosis of microorganisms (10), with an increased production of reactive oxygen intermediates (28, 29) as well as decreased cytokine secretion (24) and production of reactive nitrogen intermediates (27). Further studies have reported that cocaine enhanced neutrophil phagocytosis, increased natural killer (NK) cell activity and distribution (26), reduced the Tcell mitogen response (13), and reduced the cytotoxic ability of splenic immune cells (14). Taken together, these studies indicate that the effects of cocaine vary considerably depending on which parameter of the immune repertoire is investigated as well as the tools used to measure them.The chronic use of illicit drugs has been linked to an increased susceptibility to viral infections (3, 5). In a series of studies by Peterson et al., cocaine was reported to increase the production of p24 antigen in human immunodeficiency virus (HIV)-infected, activated peripheral blood mononuclear cells (PBMC) (18)(19)(20). This increase was taken to indicate an increase in HIV replication. Other researchers reported that cocaine increased p24 production in unstimulated PBMC but not in chronically infected mononuclear cell lines (1). Palamara et al. have described an increase in Sendai virus replication in epithelial cells cultured with cocaine in vitro, possibly caused by decreasing intracellular glutathione levels and increasing the redox state of the cells (15). Recently, our lab has described an antiviral activity of cocaine on murine peritoneal M infected with mouse hepatitis virus (MHV) in vitro (9). However, the mechanism(s) involved in this activity was not previously characterized.The principal nonspecific mechanism used by cells to inhibit . In this study, we have further characterized the effect of cocaine on virus replication in vitro. Using both prima...