Background:  Stromal cell-derived factor-1 alpha (SDF-1a) and its receptor CXCR4 play important roles in the pathogenesis of HIV-1-associated dementia (HAD). However, the underlying mechanisms regulating SDF-1a production are unknown. In this report, we investigate the role of macrophages, an important cell type in HAD pathogenesis, in mediating SDF-1 production from astrocytes. We test the hypothesis that interleukin-1b (IL-1b), produced from HIV-1-infected and immune activated monocyte-derived macrophages (MDM), is the major inducing factor for SDF-1 production from human astrocytes.

Methods:  Brain tissues from HAD subjects and HIV-1-infected subjects without neurological symptoms were measured for the presence of SDF-1 by real time polymerase chain reaction (RT-PCR). Human MDM were infected with HIV-1 macrophage-tropic viral strains, ADA, BAL, and JRFL. IL-1b production was evaluated by RT-PCR and ELISA. Human astrocytes were exposed to MDM-conditioned media (MCM) and SDF-1 production was measured by real time RT-PCR and FluoELISA. IL-1 receptor antagonist (IL-1Ra) and IL-1b siRNA were used to abrogate IL-1b-induced SDF-1 production.

Results:  SDF-1 mRNA levels are increased in brain tissues from HAD subjects (n = 6) as compared with HIV-1-infected controls (n = 7). Immune activated and/or HIV-1_ADA-infected MDM conditioned media induced substantial increases in SDF-1 production by human astrocytes. The increase of SDF-1 from astrocytes is accompanied by an increase of IL-1b in infected/activated macrophages. This effect was also observed in a panel of macrophage-tropic strains that were isolated from HIV-infected human brain including BAL and JRFL. Moreover, SDF-1 production in astrocytes mediated by MCM, is abrogated by IL-1Ra and IL-1b siRNA treatment of human MDM.

Conclusions:  These observations provide evidence that IL-1b, from HIV-1-infected and immune-activated macrophages, serves an essential role in macrophage mediated SDF-1 production from astrocytes.