{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T02:47:44Z","timestamp":1788058064816,"version":"build-2784847793"},"reference-count":101,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T00:00:00Z","timestamp":1655337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01NS079166 (SJT)"],"award-info":[{"award-number":["R01NS079166 (SJT)"]}]},{"name":"NIH","award":["R01DA036165 (SJT)"],"award-info":[{"award-number":["R01DA036165 (SJT)"]}]},{"name":"NIH","award":["19 R01NS095747 (SJT)"],"award-info":[{"award-number":["19 R01NS095747 (SJT)"]}]},{"name":"NIH","award":["R01DA050530 (SJT)"],"award-info":[{"award-number":["R01DA050530 (SJT)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Even in the era of effective antiretroviral therapies, people living with Human Immunodeficiency Virus (HIV) are burdened with debilitating neurological dysfunction, such as HIV-associated neurocognitive disorders (HAND) and HIV-associated pain, for which there are no FDA approved treatments. Disruption to the neural circuits of cognition and pain in the form of synaptic degeneration is implicated in developing these dysfunctions. Glia-mediated synaptic pruning is a mechanism of structural plasticity in the healthy central nervous system (CNS), but recently, it has been discovered that dysregulated glia-mediated synaptic pruning is the cause of synaptic degeneration, leading to maladaptive plasticity and cognitive deficits in multiple diseases of the CNS. Considering the essential contribution of activated glial cells during the development of HAND and HIV-associated pain, it is possible that glia-mediated synaptic pruning is the causative mechanism of synaptic degeneration induced by HIV. This review will analyze the known examples of synaptic pruning during disease in order to better understand how this mechanism could contribute to the progression of HAND and HIV-associated pain.<\/jats:p>","DOI":"10.3390\/cells11121943","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T01:48:12Z","timestamp":1655430492000},"page":"1943","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Aberrant Synaptic Pruning in CNS Diseases: A Critical Player in HIV-Associated Neurological Dysfunction?"],"prefix":"10.3390","volume":"11","author":[{"given":"Zachary","family":"Watson","sequence":"first","affiliation":[{"name":"Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao-Jun","family":"Tang","sequence":"additional","affiliation":[{"name":"Stony Brook University Pain and Analgesia Research Center (SPARC), Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2610","DOI":"10.1212\/WNL.0000000000010752","article-title":"Global prevalence and burden of HIV-associated neurocognitive disorder","volume":"95","author":"Wang","year":"2020","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18719","DOI":"10.7448\/IAS.17.1.18719","article-title":"Pain in people living with HIV\/AIDS: A systematic review","volume":"17","author":"Parker","year":"2014","journal-title":"J. Int. AIDS Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/B978-0-444-63849-6.00007-4","article-title":"HIV-associated neurocognitive disorder","volume":"152","author":"Smail","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"653852","DOI":"10.3389\/fphar.2021.653852","article-title":"Neuroinflammation in HIV-Related Neuropathic Pain","volume":"12","author":"Lu","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1002\/hbm.24577","article-title":"Different roles of frontal versus striatal atrophy in HIV-associated neurocognitive disorders","volume":"40","author":"Israel","year":"2019","journal-title":"Hum. Brain Mapp."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1097\/01.aids.0000218552.69834.00","article-title":"Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment","volume":"20","author":"Moore","year":"2006","journal-title":"AIDS"},{"key":"ref_7","first-page":"243","article-title":"HIV-related neuropathy: Current perspectives","volume":"5","year":"2013","journal-title":"HIV\/AIDS\u2014Res. Palliat. Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1001\/archneur.56.1.84","article-title":"Peripheral Nerve Function in HIV Infection","volume":"56","author":"Tagliati","year":"1999","journal-title":"Arch. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/j.celrep.2019.10.002","article-title":"Spontaneous Pain Disrupts Ventral Hippocampal CA1-Infralimbic Cortex Connectivity and Modulates Pain Progression in Rats with Peripheral Inflammation","volume":"29","author":"Ma","year":"2019","journal-title":"Cell Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/j.pain.2014.02.019","article-title":"Role of nucleus accumbens in neuropathic pain: Linked multi-scale evidence in the rat transitioning to neuropathic pain","volume":"155","author":"Chang","year":"2014","journal-title":"Pain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nrneurol.2016.53","article-title":"Erratum: HIV-associated neurocognitive disorder\u2014pathogenesis and prospects for treatment","volume":"12","author":"Saylor","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gelman, B.B., Chen, T., Lisinicchia, J.G., Soukup, V.M., Carmical, J.R., Starkey, J., Masliah, E., Commins, D.L., Brandt, D., and Grant, I. (2012). The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV-Associated Neurocognitive Impairment. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046178"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13041-017-0321-z","article-title":"HIV-associated synaptic degeneration","volume":"10","author":"Ru","year":"2017","journal-title":"Mol. Brain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1002\/ana.24139","article-title":"Gp120 in the pathogenesis of human immunodeficiency virus-associated pain","volume":"75","author":"Yuan","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.1750-3639.1999.tb00219.x","article-title":"Cortical Synaptic Density is Reduced in Mild to Moderate Human Immunodeficiency Virus Neurocognitive Disorder","volume":"9","author":"Everall","year":"2006","journal-title":"Brain Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s11481-016-9652-2","article-title":"Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection","volume":"11","author":"Buzhdygan","year":"2016","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1007\/s13365-019-00823-1","article-title":"Detecting cognitive impairment in HIV-infected individuals using mutual connectivity analysis of resting state functional MRI","volume":"26","author":"Abidin","year":"2020","journal-title":"J. NeuroVirology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/ana.410300410","article-title":"Physical basis of cognitive alterations in alzheimer\u2019s disease: Synapse loss is the major correlate of cognitive impairment","volume":"30","author":"Terry","year":"1991","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1002\/ana.21995","article-title":"Clinical progression in Parkinson disease and the neurobiology of axons","volume":"67","author":"Cheng","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.tins.2010.08.002","article-title":"Early synaptic pathophysiology in neurodegeneration: Insights from Huntington\u2019s disease","volume":"33","author":"Milnerwood","year":"2010","journal-title":"Trends Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1080\/13803390902881918","article-title":"Persistent neuropsychological impairment associated with West Nile virus infection","volume":"32","author":"Sadek","year":"2010","journal-title":"J. Clin. Exp. Neuropsychol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.neuron.2014.01.018","article-title":"Transmitting Pain and Itch Messages: A Contemporary View of the Spinal Cord Circuits that Generate Gate Control","volume":"82","author":"Braz","year":"2014","journal-title":"Neuron"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nrn.2017.5","article-title":"Erratum: Structural plasticity and reorganisation in chronic pain","volume":"18","author":"Kuner","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1016\/j.pain.2010.09.030","article-title":"Central sensitization: Implications for the diagnosis and treatment of pain","volume":"152","author":"Woolf","year":"2011","journal-title":"Pain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2021220118","DOI":"10.1073\/pnas.2021220118","article-title":"A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior","volume":"118","author":"Tashima","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1750-1326-8-23","article-title":"The synaptic maintenance problem: Membrane recycling, Ca2+ homeostasis and late onset degeneration","volume":"8","author":"Bezprozvanny","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/nature01273","article-title":"Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex","volume":"420","author":"Trachtenberg","year":"2002","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1523\/JNEUROSCI.3121-13.2014","article-title":"Local Pruning of Dendrites and Spines by Caspase-3-Dependent and Proteasome-Limited Mechanisms","volume":"34","author":"Wang","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1007\/s11064-018-2502-2","article-title":"Scaling Synapses in the Presence of HIV","volume":"44","author":"Green","year":"2018","journal-title":"Neurochem. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/BF03036448","article-title":"Role of activated astrocytes in neuronal damage: Potential links to HIV-1-associated dementia","volume":"7","author":"Deshpande","year":"2005","journal-title":"Neurotox. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1750-3639.1991.tb00656.x","article-title":"Neuropathology of Human Immunodeficiency Virus Infection","volume":"1","author":"Budka","year":"1991","journal-title":"Brain Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/nn1218","article-title":"Neural activity and the dynamics of central nervous system development","volume":"7","author":"Hua","year":"2004","journal-title":"Nat. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1002\/dneu.22814","article-title":"Microglia regulate synaptic development and plasticity","volume":"81","author":"Andoh","year":"2021","journal-title":"Dev. Neurobiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1126\/science.1202529","article-title":"Synaptic Pruning by Microglia Is Necessary for Normal Brain Development","volume":"333","author":"Paolicelli","year":"2011","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.neuron.2012.03.026","article-title":"Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner","volume":"74","author":"Schafer","year":"2012","journal-title":"Neuron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/nature12776","article-title":"Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways","volume":"504","author":"Chung","year":"2013","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Schafer, D.P., Lehrman, E.K., Heller, C.T., and Stevens, B. (2014). An Engulfment Assay: A Protocol to Assess Interactions between CNS Phagocytes and Neurons. J. Vis. Exp., 51482.","DOI":"10.3791\/51482"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1146\/annurev-neuro-070918-050306","article-title":"Neuron-Glia Signaling in Synapse Elimination","volume":"42","author":"Wilton","year":"2019","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1126\/science.aaz2288","article-title":"Microglia mediate forgetting via complement-dependent synaptic elimination","volume":"367","author":"Wang","year":"2020","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.neuron.2012.10.037","article-title":"Nuclear Calcium Signaling in Spinal Neurons Drives a Genomic Program Required for Persistent Inflammatory Pain","volume":"77","author":"Simonetti","year":"2013","journal-title":"Neuron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1126\/science.aal3589","article-title":"Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development","volume":"359","author":"Vainchtein","year":"2018","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.conb.2015.12.004","article-title":"New insights on the role of microglia in synaptic pruning in health and disease","volume":"36","author":"Hong","year":"2015","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"262","DOI":"10.3389\/fimmu.2015.00262","article-title":"Complement System Part I\u2014Molecular Mechanisms of Activation and Regulation","volume":"6","author":"Merle","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.cell.2007.10.036","article-title":"The Classical Complement Cascade Mediates CNS Synapse Elimination","volume":"131","author":"Stevens","year":"2007","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15106","DOI":"10.1523\/JNEUROSCI.1167-12.2012","article-title":"Deficiency of the Microglial Receptor CX3CR1 Impairs Postnatal Functional Development of Thalamocortical Synapses in the Barrel Cortex","volume":"32","author":"Hoshiko","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/s41593-019-0419-y","article-title":"Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling","volume":"22","author":"Gunner","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e105380","DOI":"10.15252\/embj.2020105380","article-title":"Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia","volume":"39","author":"Perrucci","year":"2020","journal-title":"EMBO J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.molmed.2017.03.008","article-title":"TREM2, Microglia, and Neurodegenerative Diseases","volume":"23","author":"Yeh","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.immuni.2018.04.016","article-title":"The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity","volume":"48","author":"Filipello","year":"2018","journal-title":"Immunity"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1084\/jem.20041611","article-title":"Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2","volume":"201","author":"Takahashi","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11138","DOI":"10.1523\/JNEUROSCI.1238-16.2016","article-title":"TREM2\/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain","volume":"36","author":"Kobayashi","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1084\/jem.20160844","article-title":"Soluble TREM2 induces inflammatory responses and enhances microglial survival","volume":"214","author":"Zhong","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41467-017-00037-1","article-title":"Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway","volume":"8","author":"Morizawa","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5185","DOI":"10.1523\/JNEUROSCI.3850-15.2016","article-title":"Megf10 Is a Receptor for C1Q That Mediates Clearance of Apoptotic Cells by Astrocytes","volume":"36","author":"Iram","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Hamon, Y., Trompier, R., Ma, Z., Venegas, V., Pophillat, M., Mignotte, V., Zhou, Z., and Chimini, G. (2006). Cooperation between Engulfment Receptors: The Case of ABCA1 and MEGF10. PLoS ONE, 1.","DOI":"10.1371\/journal.pone.0000120"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1002\/glia.23664","article-title":"TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment","volume":"67","author":"Jay","year":"2019","journal-title":"Glia"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.1074069","article-title":"Alzheimer\u2019s Disease Is a Synaptic Failure","volume":"298","author":"Selkoe","year":"2002","journal-title":"Science"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1093\/brain\/awaa406","article-title":"Three-dimensional analysis of synaptic organization in the hippocampal CA1 field in Alzheimer\u2019s disease","volume":"144","author":"DeFelipe","year":"2021","journal-title":"Brain"},{"key":"ref_60","first-page":"1","article-title":"TREM2 promotes A\u03b2 phagocytosis by upregulating C\/EBP\u03b1-dependent CD36 expression in microglia","volume":"7","author":"Kim","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1084\/jem.20151948","article-title":"TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques","volume":"213","author":"Wang","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.pneurobio.2016.01.001","article-title":"Astrogliosis: An integral player in the pathogenesis of Alzheimer\u2019s disease","volume":"144","author":"Osborn","year":"2016","journal-title":"Prog. Neurobiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-018-0298-9","article-title":"New insights into the role of TREM2 in Alzheimer\u2019s disease","volume":"13","author":"Gratuze","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4954","DOI":"10.1172\/JCI138179","article-title":"Impact of TREM2R47H variant on tau pathology\u2013induced gliosis and neurodegeneration","volume":"130","author":"Gratuze","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1126\/science.aad8373","article-title":"Complement and microglia mediate early synapse loss in Alzheimer mouse models","volume":"352","author":"Hong","year":"2016","journal-title":"Science"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3389\/fncel.2015.00191","article-title":"Soluble amyloid-\u00ce\u00b2 oligomers as synaptotoxins leading to cognitive impairment in Alzheimer\u00e2\u20ac\u2122s disease","volume":"9","author":"Ferreira","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/ng0694-180","article-title":"Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease","volume":"7","author":"Corder","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1126\/science.8346443","article-title":"Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families","volume":"261","author":"Corder","year":"1993","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"10186","DOI":"10.1073\/pnas.1609896113","article-title":"Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes","volume":"113","author":"Chung","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-016-0143-y","article-title":"The release and trans-synaptic transmission of Tau via exosomes","volume":"12","author":"Wang","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1002\/pro.3499","article-title":"Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross-seeding behavior","volume":"27","author":"Ghag","year":"2018","journal-title":"Protein Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"105","DOI":"10.12688\/f1000research.7404.1","article-title":"West Nile Virus Infection in the Central Nervous System","volume":"5","author":"Winkelmann","year":"2016","journal-title":"F1000Research"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Peng, B.-H., and Wang, T. (2019). West Nile Virus Induced Cell Death in the Central Nervous System. Pathogens, 8.","DOI":"10.3390\/pathogens8040215"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e00525-18","DOI":"10.1128\/JVI.00525-18","article-title":"Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis","volume":"92","author":"Seitz","year":"2018","journal-title":"J. Virol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/nature18283","article-title":"A complement\u2013microglial axis drives synapse loss during virus-induced memory impairment","volume":"534","author":"Vasek","year":"2016","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1038\/s41593-019-0427-y","article-title":"T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses","volume":"22","author":"Garber","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Maximova, O.A., Bernbaum, J.G., and Pletnev, A.G. (2016). West Nile Virus Spreads Transsynaptically within the Pathways of Motor Control: Anatomical and Ultrastructural Mapping of Neuronal Virus Infection in the Primate Central Nervous System. PLOS Neglected Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004980"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-11866-7","article-title":"Zika virus replicates in adult human brain tissue and impairs synapses and memory in mice","volume":"10","author":"Figueiredo","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Potokar, M., Jorga\u010devski, J., and Zorec, R. (2019). Astrocytes in Flavivirus Infections. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030691"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-021-02221-z","article-title":"Microglia are involved in phagocytosis and extracellular digestion during Zika virus encephalitis in young adult immunodeficient mice","volume":"18","author":"Enlow","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1016\/j.neuron.2021.05.020","article-title":"C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation","volume":"109","author":"Lall","year":"2021","journal-title":"Neuron"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1002\/glia.23199","article-title":"Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus","volume":"65","author":"Aono","year":"2017","journal-title":"Glia"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.immuni.2019.12.004","article-title":"Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease","volume":"52","author":"Werneburg","year":"2019","journal-title":"Immunity"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/ana.21697","article-title":"Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia","volume":"66","author":"Churchill","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12977-018-0462-x","article-title":"The role of exosomal transport of viral agents in persistent HIV pathogenesis","volume":"15","author":"Patters","year":"2018","journal-title":"Retrovirology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1212\/WNL.0b013e3182662073","article-title":"The Neurology of Aids, Third Edition","volume":"79","author":"Albert","year":"2012","journal-title":"Neurology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1038\/82199","article-title":"Uptake of HIV-1 Tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands","volume":"6","author":"Liu","year":"2000","journal-title":"Nat. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/s11481-015-9644-7","article-title":"HIV-1 gp120Bal down-Regulates Phosphorylated NMDA Receptor Subunit 1 in Cortical Neurons via Activation of Glutamate and Chemokine Receptors","volume":"11","author":"Ru","year":"2015","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1006\/bbrc.2001.5743","article-title":"HIV-1 Tat Causes Apoptotic Death and Calcium Homeostasis Alterations in Rat Neurons","volume":"288","author":"Bonaviaab","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1002\/(SICI)1097-4547(19970915)49:6<732::AID-JNR7>3.0.CO;2-8","article-title":"Gp120 can revert antagonism at the glycine site of NMDA receptors mediating GABA release from cultured hippocampal neurons","volume":"49","author":"Fontana","year":"1997","journal-title":"J. Neurosci. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s12031-015-0651-1","article-title":"Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV\/gp120-Induced Neuronal Damage in an In Vivo Mouse Model","volume":"58","author":"Nakanishi","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1007\/s13365-017-0584-2","article-title":"Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS research","volume":"24","author":"Thaney","year":"2017","journal-title":"J. NeuroVirology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1002\/glia.23511","article-title":"HIV Tat causes synapse loss in a mouse model of HIV-associated neurocognitive disorder that is independent of the classical complement cascade component C1q","volume":"66","author":"Hammond","year":"2018","journal-title":"Glia"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"8408","DOI":"10.1523\/JNEUROSCI.2851-18.2019","article-title":"Microglia Mediate HIV-1 gp120-Induced Synaptic Degeneration in Spinal Pain Neural Circuits","volume":"39","author":"Ru","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"7837","DOI":"10.1523\/JNEUROSCI.0226-17.2017","article-title":"A GluN2B-Selective NMDAR Antagonist Reverses Synapse Loss and Cognitive Impairment Produced by the HIV-1 Protein Tat","volume":"37","author":"Raybuck","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e27670","DOI":"10.4161\/cib.27670","article-title":"Ultrastructure of microglia-synapse interactions in the HIV-1 Tat-injected murine central nervous system","volume":"6","author":"Tremblay","year":"2013","journal-title":"Commun. Integr. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S1386-6532(02)00123-3","article-title":"Defective phagocytosis by human monocyte\/macrophages following HIV-1 infection: Underlying mechanisms and modulation by adjunctive cytokine therapy","volume":"26","author":"Kedzierska","year":"2002","journal-title":"J. Clin. Virol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s13365-016-0460-5","article-title":"The complement system, neuronal injury, and cognitive function in horizontally-acquired HIV-infected youth","volume":"22","author":"McGuire","year":"2016","journal-title":"J. NeuroVirology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-017-0794-9","article-title":"HIV induces expression of complement component C3 in astrocytes by NF-\u03baB-dependent activation of interleukin-6 synthesis","volume":"14","author":"Nitkiewicz","year":"2017","journal-title":"J. Neuroinflammation"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.2741\/1271","article-title":"Elevated expression OF IFN-gamma in the HIV-1 infected brain","volume":"9","author":"Shapshak","year":"2004","journal-title":"Front. Biosci."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Schrier, R.D., Hong, S., Crescini, M., Ellis, R., P\u00e9rez-Santiago, J., Spina, C., Letendre, S., and HNRP Group (2015). Cerebrospinal Fluid (CSF) CD8+ T-Cells That Express Interferon-Gamma Contribute to HIV Associated Neurocognitive Disorders (HAND). PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116526"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/12\/1943\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:33:10Z","timestamp":1760139190000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/12\/1943"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,16]]},"references-count":101,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["cells11121943"],"URL":"https:\/\/doi.org\/10.3390\/cells11121943","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,16]]}}}