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

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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 - Feb 27 2001

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ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Johnston, J. B., Zhang, K., Silva, C., Shalinsky, D. R., Conant, K., Ni, W., Corbett, D., Yong, V. 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