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 c...
Main Authors: | , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2007-06-01
|
Series: | Neurobiology of Disease |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996107000617 |
id |
doaj-7f884989104e465d905b7fa5fb6c4d6a |
---|---|
record_format |
Article |
spelling |
doaj-7f884989104e465d905b7fa5fb6c4d6a2021-03-20T04:54:26ZengElsevierNeurobiology of Disease1095-953X2007-06-01263661670Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicityLara Buscemi0David Ramonet1Jonathan D. Geiger2Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, 501 N. Columbia Road, Grand Forks, ND 58203, USADepartment of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, 501 N. Columbia Road, Grand Forks, ND 58203, USACorresponding author. Fax: +1 701 777 4490.; Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, 501 N. Columbia Road, Grand Forks, ND 58203, USAHIV-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. Tat1–72 and a mutant Tat1–72 lacking the neurotoxic epitope (TatΔ31–61) 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. Tat1–72 was but TatΔ31–61 was not neurotoxic when applied directly to neurons. Supernatants from U937 cells treated with either Tat1–72 or TatΔ31–61 were neurotoxic and their immunoneutralization with an anti-TNF-α antibody decreased Tat1–72- and TatΔ31–61-induced neurotoxicity. Together, these results demonstrate that the neurotoxic epitope of Tat1–72 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.http://www.sciencedirect.com/science/article/pii/S0969996107000617TNF-αHIV-1TatNeurotoxicityMacrophagesMicroglia |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lara Buscemi David Ramonet Jonathan D. Geiger |
spellingShingle |
Lara Buscemi David Ramonet Jonathan D. Geiger Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity Neurobiology of Disease TNF-α HIV-1 Tat Neurotoxicity Macrophages Microglia |
author_facet |
Lara Buscemi David Ramonet Jonathan D. Geiger |
author_sort |
Lara Buscemi |
title |
Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity |
title_short |
Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity |
title_full |
Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity |
title_fullStr |
Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity |
title_full_unstemmed |
Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity |
title_sort |
human immunodeficiency virus type-1 protein tat induces tumor necrosis factor-α-mediated neurotoxicity |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2007-06-01 |
description |
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. Tat1–72 and a mutant Tat1–72 lacking the neurotoxic epitope (TatΔ31–61) 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. Tat1–72 was but TatΔ31–61 was not neurotoxic when applied directly to neurons. Supernatants from U937 cells treated with either Tat1–72 or TatΔ31–61 were neurotoxic and their immunoneutralization with an anti-TNF-α antibody decreased Tat1–72- and TatΔ31–61-induced neurotoxicity. Together, these results demonstrate that the neurotoxic epitope of Tat1–72 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. |
topic |
TNF-α HIV-1 Tat Neurotoxicity Macrophages Microglia |
url |
http://www.sciencedirect.com/science/article/pii/S0969996107000617 |
work_keys_str_mv |
AT larabuscemi humanimmunodeficiencyvirustype1proteintatinducestumornecrosisfactoramediatedneurotoxicity AT davidramonet humanimmunodeficiencyvirustype1proteintatinducestumornecrosisfactoramediatedneurotoxicity AT jonathandgeiger humanimmunodeficiencyvirustype1proteintatinducestumornecrosisfactoramediatedneurotoxicity |
_version_ |
1724211828170424320 |