Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

HIV-1 infection causes, with increasing prevalence, neurological disorders characterized in part by neuronal cell death. The HIV-1 protein Tat has been shown to be directly and indirectly neurotoxic. Here, we tested the hypothesis that a non-neurotoxic epitope of Tat can, through actions on immune cells, increase neuronal cell death. Tat_1-72 and a mutant Tat_1-72 lacking the neurotoxic epitope (Tat_Δ31-61) concentration-dependently and markedly increased TNF-α production in macrophage-like differentiated human U937 and THP-1 cells, in mouse peritoneal macrophages and in mouse brain microglia. Tat_1-72 was but Tat_Δ31-61 was not neurotoxic when applied directly to neurons. Supernatants from U937 cells treated with either Tat_1-72 or Tat_Δ31-61 were neurotoxic and their immunoneutralization with an anti-TNF-α antibody decreased Tat_1-72- and Tat_Δ31-61-induced neurotoxicity. Together, these results demonstrate that the neurotoxic epitope of Tat_1-72 is different from the epitope that is indirectly neurotoxic following production of TNF-α from immune cells, and suggest that therapeutic interventions against TNF-α might be beneficial against HIV-1 associated neurological disorders.