Reactive astrogliosis is a key pathological aspect of neuroinflammatory disorders including human immunodeficiency virus type 1 (HIV-1)-associated neurological disease. On the basis of previous data that showedastrocytes activated with interleukin (IL)-1β induce neuronal injury, we analyzed global gene changes in IL-1β-activated human astrocytes by gene microarray. Among the up-regulated genes, CD38, a 45-kDa type II single chain transmembrane glycoprotein, was a top candidate, with a 17.24-fold change that was validated by real-time polymerase chain reaction. Key functions of CD38 include enzymatic activities and involvement in adhesion and cell signaling. Importantly, CD38+CD8+ T-cell expression is a clinical correlate for progression of HIV-1 infection and biological marker for immune activation. Thus, CD38 expression in HIV-1 and/or IL-1β-stimulated human astrocytes and human brain tissues was analyzed. IL-1β and HIV-1 activation of astrocytes enhanced CD38 mRNA levels. Both CD38 immunoreactivity and adenosine 5′-diphosphate (ADP)-ribosyl cyclase activity were up-regulated in IL-1β-activated astrocytes. CD38 knockdown using specific siRNAs significantly reduced astrocyte proinflammatory cytokine and chemokine production. However, CD38 mRNA levels were unchanged in IL-1β knockdown conditions, suggesting that IL-1β autocrine loop is not implicated in this process. Quantitative immunohistochemical analysis of HIV-seropositive without encephalitis and HIV-1 encephalitis brain tissues showed significant up-regulation of CD38, which colocalized with glial fibrillary acidic protein–positive cells in areas of inflammation. These results suggest an important role of CD38 in the regulation of astrocyte dysfunction during the neuroinflammatory processes involved in neurodegenerative/neuroinflammatory disorders such as HIV-1 encephalitis. © 2009 Wiley-Liss, Inc.