Brain macrophages/microglia and astrocytes are known to be involved in the pathogenesis of HIV-1-associated dementia (HAD). To clarify their interaction and contribution to the pathogenesis, HIV-1-infected or uninfected macrophages were used as a model of brain macrophages/microglia, and their effects on human astrocytes in vitro were examined. The culture supernatants of HIV-1-infected or uninfected macrophages induced significant astrocyte proliferation, which was annihilated with a neutralizing antibody to stromal cell-derived factor (SDF)-1 alpha or a matrix metalloprotemase (MMP) inhibitor. In these astrocytes, CXCR4, MMP, and tissue inhibitors of matrix metalloproteinase mRNA expression and SDF-1 alpha production were significantly up-regulated. The supernatants of infected macrophages were always more effective than those of uninfected cells. Moreover, the enhanced production of SDF-1 alpha was suppressed by the MMP inhibitor. These results indicate that the activated and HlV-1-infected macrophages can indirectly induce astrocyte proliferation through up-regulating SDF-1 alpha and MMP production, which implies a mechanism of astrogliosis in HAD. (c) 2005 Elsevier Inc. All rights reserved.