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Background:  Pro-inflammatory factors and neurotoxins produced by MP as a consequence of viral infection, can induce neuronal injury during HIV-1-associated dementia (HAD). Previously, we demonstrated the ability of tumor necrosis factor–related apoptosis inducing ligand (TRAIL) to induce neuronal cell death by binding to death receptors found on neurons, as well as the up-regulation TRAIL on HIV-infected and immune activated macrophages. This study explores the hypothesis that TRAIL mediates apoptosis in human neural progenitor cells, therefore altering neurogenesis during HAD.

Methods:  Brain tissues from HAD subjects and HIV-1-infected subjects without neurological symptoms were measured for the presence of TRAIL by ELISA. Human neural progenitor cells were examined for TRAIL receptor expression by both real-time PCR and immunohistochemistry. TRAIL-mediated apoptosis and the associated signaling pathways were evaluated by TUNEL assay, microarray, real-time PCR, Western blot, and RNA interference (RNAi) technology.   

Results:  TRAIL levels are significantly increased in brain tissues from HAD subjects (n = 11) as compared with HIV-1-infected controls (n = 9). TRAIL receptor 2 is highly expressed by human neural progenitor cells, yet TRAIL treatment causes minimal apoptosis (5 to 10%) in human neural progenitor cells. It was found that caspase 8 protein is minimally expressed by human neural progenitor cells, while inhibitor of apoptosis proteins (IAP) such as cIAP1 and Survivin are highly expressed. Notably, TRAIL-mediated neural progenitor cells apoptosis can be significantly enhanced by pretreatment of neural progenitor cells with actinomycin D, a nonspecific inhibitor of IAP. Further, the pre-treatment of neural progenitor cells with siRNA targeting cIAP1 significantly enhanced TRAIL-mediated apoptosis.

Conclusions:  TRAIL is significantly up-regulated in HAD. However, our results suggest that human neural progenitor cells are resistant to TRAIL-mediated apoptosis, possibly due to highly expressed IAP proteins, such as cIAP1, in this specific cell population.

Keywords: HIV-1 Associated Dementia; TRAIL; neural progenitor cells