Sindbis virus (SV) is a member of the alphaviruses which has served as a model system for studying viral encephalitis. Although astrocytes are reported to be involved in the pathogenesis of various virus-related diseases, the effects of SV on astrocyte function have not been reported. In this study we compared the effects of two strains of SV, SVA, and SVNI, which differ in their neurovirulent properties, on astrocytes with the use of cultured mouse astrocytes and the rat C6 glial cell line. We found that although both strains can similarly infect and replicate in astrocytes, they induced different changes in the function of these cells. The neurovirulent strain, SVNI, induced a decrease in cell number and a marked increase in the expression of GFAP, whereas SVA did not alter these parameters. In addition, SVNI induced the secretion of the cytokines TNF-a and IL-6, the expression of adhesion molecules, and the production of the neurotrophic factor NGF. In contrast, SVA induced smaller increases in the secretion of IL-6 and NGF but did not alter the secretion of TNF-a and the expression of the adhesion molecules. Neither virus induced the secretion of IL-2, IL-4, IL-10 and IFN-g or the expression of iNOS in the cells. These results indicate that astrocytes, similar to neurons, can serve as target cells to SV infection in the CNS. Moreover, the infection of astrocytes by SVNI leads to changes characteristic of reactive astrogliosis which may contribute to the pathogenesis of SV-induced encephalitis by enhancing the local immune response in the CNS.