Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-alpha-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(Delta31-61)) concentration-dependently and markedly increased TNF-alpha 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(Delta31-61) was not neurotoxic when applied directly to neurons. Supernatants from U937 cells treated with either Tat(1-72) or Tat(Delta31-61) were neurotoxic and their immunoneutralization with an anti-TNF-alpha antibody decreased Tat(1-72)- and Tat(Delta31-61)-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-alpha from immune cells, and suggest that therapeutic interventions against TNF-alpha might be beneficial against HIV-1 associated neurological disorders.
Buscemi
Lara
L
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, 501 N. Columbia Road, Grand Forks, ND 58203, USA.
Ramonet
David
D
Geiger
Jonathan D
JD
D015526:AIDS Dementia Complex / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000276:immunology; D015696:Gene Products, tat / Q000235:genetics / Q000276:immunology* / Q000633:toxicity; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009154:Mutation / Q000235:genetics / Q000276:immunology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000276:immunology* / Q000821:virology; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D054322:tat Gene Products, Human Immunodeficiency Virus
D000939:Epitopes; D015696:Gene Products, tat; D009498:Neurotoxins; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus