The signaling and apoptotic effects of TNF-related apoptosis-inducing ligand in HIV-1 associated dementia

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, directly mediates cell death via TRAIL receptors that are present on a variety of cells. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. Recently, we found HIV-1-infected mononuclear phagocytes (MP; perivascular macrophages and microglia) express high levels of TRAIL and mediate neuronal apoptosis. We hypothesized that TRAIL is increased and serves as a critical component of neurotoxicity in HIV-1 associated dementia (HAD), a chronic disease state that manifests as cognitive impairment during advanced HIV-1 infection.; TRAIL is not typically expressed in the central nervous system, but we found it can be induced in neuroinflammatory conditions. In post-mortem samples, TRAIL protein and mRNA in HIV-1 encephalitis patients were higher compared to HIV-1 serum-positive individuals without encephalitis and HIV-1 serum-negative samples. We focused on macrophages and astrocytes to determine the mechanisms behind TRAIL upregulation in HAD. First, macrophages expressed the highest levels of TRAIL among all tested resident cell types in the CNS. Type I interferons and Interferon regulatory factor 7 were found to be critical to TRAIL regulation in macrophages during HIV-1 infection. Second, HIV-1-infected and/or immune activated macrophages released TNF-alpha; TNF-alpha activated c-Jun N-terminal kinase pathway and led to TRAIL expression in astrocytes. These results provide evidence concerning the direct neurotoxic potential of activated MP and astrocytes in HAD pathogenesis.; We tested the effects of TRAIL stimulation on HIV-1-infected macrophages. TRAIL stimulation induced significant levels of apoptosis in HIV-1-infected macrophages, but had a minimal effect on uninfected macrophages. The increased susceptibility to TRAIL-induced apoptosis was due to inhibition of Akt-1 phosphorylation after HIVA infection. These findings suggest the induction of TRAIL may be part of the innate immune response to HIV-1 infection. In summary, the signaling and apoptotic effects of TRAIL links activated MP to the neurodegenerative processes of HAD. Investigations on the regulation of TRAIL may have implications for better understanding HIVA neuropathogenesis and in developing effective adjunctive therapies.