HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors
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 d...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-01-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996112003002 |
| _version_ | 1818352353931165696 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jeffrey A. Rumbaugh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T18:52:18Z |
| format | Article |
| id | doaj.art-a490248892804d1ea9209d44855c0247 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T18:52:18Z |
| publishDate | 2013-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-a490248892804d1ea9209d44855c02472022-12-21T23:34:55ZengElsevierNeurobiology of Disease1095-953X2013-01-0149169176HIV immune complexes prevent excitotoxicity by interaction with NMDA receptorsJeffrey A. Rumbaugh0Muznabanu Bachani1Wenxue Li2Tracy R. Butler3Katherine J. Smith4Mario A. Bianchet5Tongguang Wang6Mark A. Prendergast7Ned Sacktor8Avindra Nath9Department of Neurology, Emory University, Atlanta, GA, USA; Corresponding author at: 1670 Clairmont Road, Mailstop 11B, Decatur, GA 30033, USA. Fax: +1 404 728 4715.Department of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USADepartment of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USADepartment of Psychology, University of Kentucky, Lexington, KY, USADepartment of Psychology, University of Kentucky, Lexington, KY, USADepartment of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USA; Department of Biophysics & Biophysical Chemistry, Johns Hopkins University, Baltimore, MD, USADepartment of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USADepartment of Psychology, University of Kentucky, Lexington, KY, USADepartment of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USADepartment of Neurology and Neuroscience, Johns Hopkins University, Baltimore, MD, USAPurpose: 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.http://www.sciencedirect.com/science/article/pii/S0969996112003002NeurotoxicityNeurovirologyDementiaNeuroprotectionGlutamateNeutralizing antibodies |
| spellingShingle | 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 HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors Neurobiology of Disease Neurotoxicity Neurovirology Dementia Neuroprotection Glutamate Neutralizing antibodies |
| title | HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors |
| title_full | HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors |
| title_fullStr | HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors |
| title_full_unstemmed | HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors |
| title_short | HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors |
| title_sort | hiv immune complexes prevent excitotoxicity by interaction with nmda receptors |
| topic | Neurotoxicity Neurovirology Dementia Neuroprotection Glutamate Neutralizing antibodies |
| url | http://www.sciencedirect.com/science/article/pii/S0969996112003002 |
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