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

Lara Buscemi, David Ramonet, Jonathan D. Geiger

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)661-670
Number of pages10
JournalNeurobiology of Disease
Volume26
Issue number3
DOIs
StatePublished - Jun 1 2007

Fingerprint

Human Immunodeficiency Virus Proteins
HIV-1
Epitopes
Tumor Necrosis Factor-alpha
Nervous System Diseases
Cell Death
U937 Cells
Peritoneal Macrophages
Microglia
HIV Infections
Anti-Idiotypic Antibodies
Macrophages
Neurons
Brain

Keywords

  • HIV-1
  • Inflammation
  • Macrophages
  • Microglia
  • Neurotoxicity
  • THP-1 cells
  • TNF-α
  • Tat
  • U937 cells

ASJC Scopus subject areas

  • Neurology

Cite this

Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity. / Buscemi, Lara; Ramonet, David; Geiger, Jonathan D.

In: Neurobiology of Disease, Vol. 26, No. 3, 01.06.2007, p. 661-670.

Research output: Contribution to journalArticle

@article{f6444dea2f674e21947a6da8626e0c99,
title = "Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity",
abstract = "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.",
keywords = "HIV-1, Inflammation, Macrophages, Microglia, Neurotoxicity, THP-1 cells, TNF-α, Tat, U937 cells",
author = "Lara Buscemi and David Ramonet and Geiger, {Jonathan D.}",
year = "2007",
month = "6",
day = "1",
doi = "10.1016/j.nbd.2007.03.004",
language = "English (US)",
volume = "26",
pages = "661--670",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

AU - Buscemi, Lara

AU - Ramonet, David

AU - Geiger, Jonathan D.

PY - 2007/6/1

Y1 - 2007/6/1

N2 - 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.

AB - 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.

KW - HIV-1

KW - Inflammation

KW - Macrophages

KW - Microglia

KW - Neurotoxicity

KW - THP-1 cells

KW - TNF-α

KW - Tat

KW - U937 cells

UR - http://www.scopus.com/inward/record.url?scp=34248592116&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34248592116&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2007.03.004

DO - 10.1016/j.nbd.2007.03.004

M3 - Article

C2 - 17451964

AN - SCOPUS:34248592116

VL - 26

SP - 661

EP - 670

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

IS - 3

ER -