HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors

Jeffrey A. Rumbaugh, Muznabanu Bachani, Wenxue Li, Tracy R. Butler, Katherine J. Smith, Mario A. Bianchet, Tongguang Wang, Mark A. Prendergast, Ned Sacktor, Avindra Nath

Research output: Contribution to journalArticle

Abstract

Purpose: Human immunodeficiency virus-1 (HIV)-associated neurocognitive disorder (HAND) is a neurodegenerative disease for which there is no available neuroprotective therapy. Viral proteins, such as Tat, have been implicated as agents of neurotoxicity via multiple mechanisms, including effects by directly binding to the NMDA receptor. We evaluated the ability of the immune response against Tat to modulate neurotoxicity at glutamate receptors. Methods: Neurotoxicity was measured in primary neuronal-glial cultures and in hippocampal slice cultures. We used immunoprecipitation experiments to demonstrate interaction between Tat, NMDA receptor, and anti-Tat antibody. Using known structures of Tat and NMDA receptors, we developed a model of their interactions. Results: Antibodies to Tat attenuated Tat-mediated neurotoxicity. Interestingly, Tat immune complexes also blocked neurotoxicity caused by NMDA receptor agonists but not kainate/AMPA receptor agonists. Neither Tat nor antibody alone blocked the excitotoxic effect, nor did an unrelated antigen-antibody complex. The protective effect of the Tat immune complexes was also lost when Tat was modified by nitrosylation or by using a deletion mutant of Tat. Conclusions: The ability of viral immune complexes to interact with NMDA receptors and prevent excitotoxicity represents a novel host defense mechanism. Host immune responses may influence host susceptibility to various effects of viral proteins, modulating HIV complications, such as onset of HAND. These observations provide rationale for development of vaccine therapies targeting Tat for prevention of HAND.

Original languageEnglish (US)
Pages (from-to)169-176
Number of pages8
JournalNeurobiology of Disease
Volume49
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Dementia
  • Glutamate
  • Neuroprotection
  • Neurotoxicity
  • Neurovirology
  • Neutralizing antibodies

ASJC Scopus subject areas

  • Neurology

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  • Cite this

    Rumbaugh, J. A., Bachani, M., Li, W., Butler, T. R., Smith, K. J., Bianchet, M. A., Wang, T., Prendergast, M. A., Sacktor, N., & Nath, A. (2013). HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors. Neurobiology of Disease, 49(1), 169-176. https://doi.org/10.1016/j.nbd.2012.08.013