HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors

James B. Johnston, Kunyan Zhang, Claudia Silva, David R. Shalinsky, Katherine Conant, Weimin Ni, Dale Corbett, Voon Wee Yong, Christopher Power

Research output: Contribution to journalArticle

Abstract

The release of potentially neurotoxic molecules by HIV-infected brain macrophages is accompanied by neuronal injury and death that results in the development of HIV-associated dementia (HAD). Among the potential neurotoxins implicated in the development of HAD is the HIV-1 transactivating protein, Tat. To investigate the mechanism by which Tat causes neurotoxicity, brain-derived Tat sequences from nondemented (Tat-ND) and demented (Tat-HAD) AIDS patients, which differed primarily in the augmenting region of Tat, were expressed in U937 monoblastoid cells and primary buman macrophages. Cells expressing Tat-HAD protein exhibited elevated matrix metalloproteinase (MMP)-2 and -7 release and activation, but cells expressing Tat-ND did not exhibit enhanced MMP expression. Conditioned media from Tat-HAD-transfected cells caused significantly greater neuronal death (15.4 ± 4.3%) than did Tat-ND (4.4 ± 2.1%) or nontransfected (2.1 ± 0.8%) cell-derived conditioned media. The neurotoxicity induced by Tat-HAD was inhibited by anti-MMP-2 or -7 antibodies (p ± 0.005) but not by antibodies against MMP-9 or Tat. Similarly, scid/nod mice receiving striatal implants of Tat-HAD-transfected cells exhibited greater neurobehavioral abnormalities and neuronal loss (p <0.005) than did animals receiving Tat-ND or nontransfected cells, which were reduced by treatment with the MMP inhibitor prinomastat (p <0.005). These findings indicate that Tat causes neuronal death through an indirect mechanism that is Tat sequence dependent and involves the induction of MMPs.

Original languageEnglish (US)
Pages (from-to)230-241
Number of pages12
JournalAnnals of Neurology
Volume49
Issue number2
DOIs
StatePublished - 2001
Externally publishedYes

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AIDS Dementia Complex
Matrix Metalloproteinase Inhibitors
HIV-1
Matrix Metalloproteinase 2
Conditioned Culture Medium
Matrix Metalloproteinases
Macrophages
Matrix Metalloproteinase 7
tat Gene Products
Corpus Striatum
U937 Cells
Antibodies
Matrix Metalloproteinase 9
Neurotoxins
Brain
Cause of Death
Acquired Immunodeficiency Syndrome
HIV
Wounds and Injuries

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Johnston, J. B., Zhang, K., Silva, C., Shalinsky, D. R., Conant, K., Ni, W., ... Power, C. (2001). HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors. Annals of Neurology, 49(2), 230-241. https://doi.org/10.1002/1531-8249(20010201)49:2<230::AID-ANA43>3.0.CO;2-O

HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors. / Johnston, James B.; Zhang, Kunyan; Silva, Claudia; Shalinsky, David R.; Conant, Katherine; Ni, Weimin; Corbett, Dale; Yong, Voon Wee; Power, Christopher.

In: Annals of Neurology, Vol. 49, No. 2, 2001, p. 230-241.

Research output: Contribution to journalArticle

Johnston, JB, Zhang, K, Silva, C, Shalinsky, DR, Conant, K, Ni, W, Corbett, D, Yong, VW & Power, C 2001, 'HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors', Annals of Neurology, vol. 49, no. 2, pp. 230-241. https://doi.org/10.1002/1531-8249(20010201)49:2<230::AID-ANA43>3.0.CO;2-O
Johnston, James B. ; Zhang, Kunyan ; Silva, Claudia ; Shalinsky, David R. ; Conant, Katherine ; Ni, Weimin ; Corbett, Dale ; Yong, Voon Wee ; Power, Christopher. / HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors. In: Annals of Neurology. 2001 ; Vol. 49, No. 2. pp. 230-241.
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