title: HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurology, Emory University, Atlanta, GA, USA. Electronic address: jrumbau@emory.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Rumbaugh
authors.affiliation: Department of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Muznabanu
authors.initials: M
authors.lastname: Bachani
authors.affiliation: Department of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Wenxue
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY, USA.
authors.forename: Tracy R
authors.initials: TR
authors.lastname: Butler
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY, USA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Smith
authors.affiliation: Department of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USA; Department of Biophysics & Biophysical Chemistry, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Bianchet
authors.affiliation: Department of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Tongguang
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Prendergast
authors.affiliation: Department of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ned
authors.initials: N
authors.lastname: Sacktor
authors.affiliation: Department of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008297:Male; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology; D009474:Neurons / Q000187:drug effects / Q000276:immunology; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000819:agonists / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism*; D017384:Sequence Deletion; D046509:Tissue Culture Techniques; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000906:Antibodies; D000936:Antigen-Antibody Complex; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D054322:tat Gene Products, Human Immunodeficiency Virus