{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T04:53:58Z","timestamp":1778907238054,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013180","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000}}],"reference-count":107,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["RO1NS126091"],"award-info":[{"award-number":["RO1NS126091"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["RO1NS040237"],"award-info":[{"award-number":["RO1NS040237"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    The effects of antiretroviral therapy (ART) and treatment interruption on myeloid cell egress from the central nervous system (CNS) during human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection remain poorly defined. We hypothesized that CNS macrophages normally traffic out of the CNS, accumulate during viral infection and inflammation, and are released as inflammation resolves. To test this, we administered intracisternal (i.c.) injections of two different colored fluorescent superparamagnetic iron oxide nanoparticles (SPION) to SIV-infected macaques either early in infection (12\u201314 dpi) or 30 days before necropsy. SPION are preferentially taken up by perivascular, meningeal, and choroid plexus macrophages, enabling us to track macrophage turnover, infection, and migration. In non-infected macaques, SPION\n                    <jats:sup>+<\/jats:sup>\n                    macrophages trafficked from the CNS to peripheral sites including the deep cervical lymph node (dCLN), lumbar lymph nodes, spleen, and dorsal root ganglia (DRG). With SIV infection, these cells accumulated in the CNS and showed reduced peripheral trafficking. ART decreased the number of SPION+ perivascular macrophages, and to a lesser extent, meningeal or choroid plexus macrophages. After ART interruption, SPION\n                    <jats:sup>+<\/jats:sup>\n                    perivascular and choroid plexus macrophage numbers remained stable, whereas SPION\n                    <jats:sup>+<\/jats:sup>\n                    meningeal macrophages increased. ART eliminated SIV-RNA\n                    <jats:sup>+<\/jats:sup>\n                    perivascular macrophages, leaving few- scattered SIV-RNA\n                    <jats:sup>+<\/jats:sup>\n                    cells in the meninges and choroid plexus. Following ART interruption, perivascular macrophages remained virus-negative, but scattered viral RNA\n                    <jats:sup>+<\/jats:sup>\n                    meningeal macrophages persisted. In non-infected macaques, SPION\n                    <jats:sup>+<\/jats:sup>\n                    macrophages trafficked to the dCLN, spleen, and DRG, but this trafficking diminished with SIV infection and AIDS with SIVE. Importantly, SIV-RNA\n                    <jats:sup>+<\/jats:sup>\n                    SPION\n                    <jats:sup>+<\/jats:sup>\n                    macrophages that exited the CNS were cleared by ART and did not reappear after treatment interruption. Using two differently colored SPION to assess establishment of CNS viral reservoirs, we observed higher numbers of early-labeled macrophages within and outside the CNS in animals with AIDS and SIVE, ART treatment, and ART interruption. These findings support a model in which SIV-infected perivascular macrophages seed an early CNS viral reservoir, while the meninges and choroid plexus undergo continual viral seeding during infection. ART reduces trafficking of infected macrophages out of the CNS and clears the perivascular macrophage reservoir, but SIV-RNA+ meningeal macrophages can persist, in low numbers, and can rebound after ART interruption.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013180","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T19:01:42Z","timestamp":1764615702000},"page":"e1013180","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Resolving inflammation: The impact of antiretroviral therapy on macrophage traffic in and out of the CNS"],"prefix":"10.1371","volume":"21","author":[{"given":"Zoey K.","family":"Wallis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecily C.","family":"Midkiff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miaoyun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Autissier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soon Ok","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Addison Q.","family":"Amadeck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maia","family":"Jakubowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tricia H.","family":"Burdo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew D.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingsheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xavier","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert V.","family":"Blair","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6394-539X","authenticated-orcid":true,"given":"Kenneth C.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"issue":"4","key":"ppat.1013180.ref001","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nrneurol.2016.27","article-title":"HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment","volume":"12","author":"D Saylor","year":"2016","journal-title":"Nat Rev Neurol"},{"issue":"21","key":"ppat.1013180.ref002","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1056\/NEJM199905273402102","article-title":"Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy","volume":"340","author":"MR Furtado","year":"1999","journal-title":"N Engl J Med"},{"issue":"1","key":"ppat.1013180.ref003","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/71569","article-title":"Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy","volume":"6","author":"ME Sharkey","year":"2000","journal-title":"Nat Med"},{"issue":"6","key":"ppat.1013180.ref004","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1128\/JCM.40.6.2089-2094.2002","article-title":"Detection of replication-competent human immunodeficiency virus type 1 (HIV-1) in cultures from patients with levels of HIV-1 RNA in plasma suppressed to less than 500 or 50 copies per milliliter","volume":"40","author":"LM Demeter","year":"2002","journal-title":"J Clin Microbiol"},{"issue":"5314","key":"ppat.1013180.ref005","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1126\/science.276.5314.960","article-title":"Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection","volume":"276","author":"W Cavert","year":"1997","journal-title":"Science"},{"issue":"5","key":"ppat.1013180.ref006","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1189\/jlb.0503204","article-title":"The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection","volume":"74","author":"S Crowe","year":"2003","journal-title":"J Leukoc Biol"},{"issue":"17","key":"ppat.1013180.ref007","doi-asserted-by":"crossref","first-page":"11343","DOI":"10.1128\/JVI.79.17.11343-11352.2005","article-title":"Phylodynamic analysis of human immunodeficiency virus type 1 in distinct brain compartments provides a model for the neuropathogenesis of AIDS","volume":"79","author":"M Salemi","year":"2005","journal-title":"J Virol"},{"issue":"2","key":"ppat.1013180.ref008","doi-asserted-by":"crossref","first-page":"110","DOI":"10.2174\/1570162X13666151029102413","article-title":"Phylogenetics and Phyloanatomy of HIV\/SIV Intra-Host Compartments and Reservoirs: The Key Role of the Central Nervous System","volume":"14","author":"M Salemi","year":"2016","journal-title":"Curr HIV Res"},{"issue":"1","key":"ppat.1013180.ref009","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1097\/COH.0b013e3283412413","article-title":"A simian immunodeficiency virus macaque model of highly active antiretroviral treatment: viral latency in the periphery and the central nervous system","volume":"6","author":"JE Clements","year":"2011","journal-title":"Curr Opin HIV AIDS"},{"issue":"2","key":"ppat.1013180.ref010","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1080\/13550280590922829","article-title":"The central nervous system is a viral reservoir in simian immunodeficiency virus--infected macaques on combined antiretroviral therapy: a model for human immunodeficiency virus patients on highly active antiretroviral therapy","volume":"11","author":"JE Clements","year":"2005","journal-title":"J Neurovirol"},{"issue":"5","key":"ppat.1013180.ref011","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/s41564-023-01349-3","article-title":"Monocyte-derived macrophages contain persistent latent HIV reservoirs","volume":"8","author":"RT Veenhuis","year":"2023","journal-title":"Nat Microbiol"},{"issue":"2","key":"ppat.1013180.ref012","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1006\/exnr.2000.7618","article-title":"Turnover of rat brain perivascular cells","volume":"168","author":"I Bechmann","year":"2001","journal-title":"Exp Neurol"},{"issue":"7","key":"ppat.1013180.ref013","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/ni.3423","article-title":"Origin, fate and dynamics of macrophages at central nervous system interfaces","volume":"17","author":"T Goldmann","year":"2016","journal-title":"Nat Immunol"},{"issue":"4837","key":"ppat.1013180.ref014","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1126\/science.3276004","article-title":"Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo","volume":"239","author":"WF Hickey","year":"1988","journal-title":"Science"},{"issue":"3","key":"ppat.1013180.ref015","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1097\/00005072-199205000-00002","article-title":"Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras","volume":"51","author":"WF Hickey","year":"1992","journal-title":"J Neuropathol Exp Neurol"},{"issue":"8","key":"ppat.1013180.ref016","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1084\/jem.193.8.905","article-title":"Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS","volume":"193","author":"KC Williams","year":"2001","journal-title":"J Exp Med"},{"issue":"6","key":"ppat.1013180.ref017","doi-asserted-by":"crossref","first-page":"423","DOI":"10.3109\/13550289609146909","article-title":"Neuroinvasion by simian immunodeficiency virus coincides with increased numbers of perivascular macrophages\/microglia and intrathecal immune activation","volume":"2","author":"JH Lane","year":"1996","journal-title":"J Neurovirol"},{"key":"ppat.1013180.ref018","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.conb.2019.11.010","article-title":"Meningeal lymphatics, immunity and neuroinflammation","volume":"62","author":"N Frederick","year":"2020","journal-title":"Curr Opin Neurobiol"},{"issue":"7560","key":"ppat.1013180.ref019","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature14432","article-title":"Structural and functional features of central nervous system lymphatic vessels","volume":"523","author":"A Louveau","year":"2015","journal-title":"Nature"},{"issue":"6","key":"ppat.1013180.ref020","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.it.2019.04.004","article-title":"Monocytes Inadequately Fill In for Meningeal Macrophages","volume":"40","author":"E Song","year":"2019","journal-title":"Trends Immunol"},{"issue":"1","key":"ppat.1013180.ref021","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.meegid.2010.10.016","article-title":"HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues","volume":"11","author":"SL Lamers","year":"2011","journal-title":"Infect Genet Evol"},{"issue":"11","key":"ppat.1013180.ref022","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1016\/j.tins.2021.07.002","article-title":"Macrophages on the margin: choroid plexus immune responses","volume":"44","author":"J Cui","year":"2021","journal-title":"Trends Neurosci"},{"issue":"6","key":"ppat.1013180.ref023","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1007\/s00018-020-03706-5","article-title":"Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics","volume":"78","author":"ST Proulx","year":"2021","journal-title":"Cell Mol Life Sci"},{"issue":"3","key":"ppat.1013180.ref024","first-page":"609","article-title":"Localization of simian immunodeficiency virus in the central nervous system of rhesus monkeys","volume":"139","author":"AA Lackner","year":"1991","journal-title":"Am J Pathol"},{"issue":"7","key":"ppat.1013180.ref025","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1097\/01.aids.0000166090.31693.aa","article-title":"Compartmentalization of HIV-1 in the central nervous system: role of the choroid plexus","volume":"19","author":"EJ Burkala","year":"2005","journal-title":"AIDS"},{"issue":"4","key":"ppat.1013180.ref026","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1097\/00005072-199507000-00003","article-title":"HIV infection of human choroid plexus: a possible mechanism of viral entry into the CNS","volume":"54","author":"MF Falangola","year":"1995","journal-title":"J Neuropathol Exp Neurol"},{"issue":"6","key":"ppat.1013180.ref027","doi-asserted-by":"crossref","first-page":"670","DOI":"10.3109\/13550289909021295","article-title":"HIV infection of choroid plexus in AIDS and asymptomatic HIV-infected patients suggests that the choroid plexus may be a reservoir of productive infection","volume":"5","author":"CK Petito","year":"1999","journal-title":"J Neurovirol"},{"issue":"4","key":"ppat.1013180.ref028","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1002\/ana.410250414","article-title":"Human choroid plexus cells can be latently infected with human immunodeficiency virus","volume":"25","author":"JM Harouse","year":"1989","journal-title":"Ann Neurol"},{"issue":"6","key":"ppat.1013180.ref029","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.immuni.2017.06.007","article-title":"Myeloid Cells in the Central Nervous System","volume":"46","author":"J Herz","year":"2017","journal-title":"Immunity"},{"issue":"1","key":"ppat.1013180.ref030","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1084\/jem.20180199","article-title":"Immune cells and CNS physiology: Microglia and beyond","volume":"216","author":"GT Norris","year":"2019","journal-title":"J Exp Med"},{"key":"ppat.1013180.ref031","doi-asserted-by":"crossref","first-page":"32900","DOI":"10.1038\/srep32900","article-title":"Proliferation of Perivascular Macrophages Contributes to the Development of Encephalitic Lesions in HIV-Infected Humans and in SIV-Infected Macaques","volume":"6","author":"AR Filipowicz","year":"2016","journal-title":"Sci Rep"},{"issue":"6","key":"ppat.1013180.ref032","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1080\/135502801753248114","article-title":"CNS invasion by CD14+\/CD16+ peripheral blood-derived monocytes in HIV dementia: perivascular accumulation and reservoir of HIV infection","volume":"7","author":"T Fischer-Smith","year":"2001","journal-title":"J Neurovirol"},{"issue":"6","key":"ppat.1013180.ref033","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1016\/j.ajpath.2015.01.033","article-title":"SIV encephalitis lesions are composed of CD163(+) macrophages present in the central nervous system during early SIV infection and SIV-positive macrophages recruited terminally with AIDS","volume":"185","author":"BT Nowlin","year":"2015","journal-title":"Am J Pathol"},{"issue":"5","key":"ppat.1013180.ref034","first-page":"2121","article-title":"Recently infiltrating MAC387(+) monocytes\/macrophages a third macrophage population involved in SIV and HIV encephalitic lesion formation","volume":"178","author":"C Soulas","year":"2011","journal-title":"Am J Pathol"},{"issue":"5","key":"ppat.1013180.ref035","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1172\/JCI41911","article-title":"Trafficking of immune cells in the central nervous system","volume":"120","author":"EH Wilson","year":"2010","journal-title":"J Clin Invest"},{"issue":"7","key":"ppat.1013180.ref036","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/nri1130","article-title":"Three or more routes for leukocyte migration into the central nervous system","volume":"3","author":"RM Ransohoff","year":"2003","journal-title":"Nat Rev Immunol"},{"key":"ppat.1013180.ref037","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1600-065X.2006.00433.x","article-title":"Immune cell migration as a means to control immune privilege: lessons from the CNS and tumors","volume":"213","author":"P Mrass","year":"2006","journal-title":"Immunol Rev"},{"issue":"5","key":"ppat.1013180.ref038","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.2353\/ajpath.2009.081010","article-title":"Genetically modified CD34+ hematopoietic stem cells contribute to turnover of brain perivascular macrophages in long-term repopulated primates","volume":"174","author":"C Soulas","year":"2009","journal-title":"Am J Pathol"},{"issue":"10","key":"ppat.1013180.ref039","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1046\/j.0953-816x.2001.01793.x","article-title":"Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages","volume":"14","author":"I Bechmann","year":"2001","journal-title":"Eur J Neurosci"},{"issue":"6","key":"ppat.1013180.ref040","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1084\/jem.20180247","article-title":"Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia","volume":"215","author":"JC Cronk","year":"2018","journal-title":"J Exp Med"},{"issue":"6553","key":"ppat.1013180.ref041","doi-asserted-by":"crossref","DOI":"10.1126\/science.abf7844","article-title":"Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma","volume":"373","author":"A Cugurra","year":"2021","journal-title":"Science"},{"issue":"1","key":"ppat.1013180.ref042","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/glia.440070106","article-title":"Bone marrow derived elements and resident microglia in brain inflammation","volume":"7","author":"H Lassmann","year":"1993","journal-title":"Glia"},{"issue":"12","key":"ppat.1013180.ref043","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1004533","article-title":"Anti-\u03b14 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection","volume":"10","author":"JH Campbell","year":"2014","journal-title":"PLoS Pathog"},{"issue":"7","key":"ppat.1013180.ref044","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1016\/j.ajpath.2016.03.007","article-title":"\u03b14-Integrin Antibody Treatment Blocks Monocyte\/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy","volume":"186","author":"JR Lakritz","year":"2016","journal-title":"Am J Pathol"},{"issue":"7","key":"ppat.1013180.ref045","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.115.001932","article-title":"Anti-\u03b14 Integrin Antibody Blocks Monocyte\/Macrophage Traffic to the Heart and Decreases Cardiac Pathology in a SIV Infection Model of AIDS","volume":"4","author":"JA Walker","year":"2015","journal-title":"J Am Heart Assoc"},{"issue":"11","key":"ppat.1013180.ref046","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1016\/j.ajpath.2025.07.014","article-title":"Novel perineural pathways and dynamics of simian immunodeficiency virus-infected macrophages traffic out of the central nervous system","volume":"195","author":"Z Wallis","year":"2025","journal-title":"Am J Pathol"},{"key":"ppat.1013180.ref047","doi-asserted-by":"crossref","first-page":"655052","DOI":"10.3389\/fphar.2021.655052","article-title":"CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges","volume":"12","author":"SP das Neves","year":"2021","journal-title":"Front Pharmacol"},{"issue":"2","key":"ppat.1013180.ref048","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1182\/blood-2005-01-0154","article-title":"How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes","volume":"107","author":"E Hatterer","year":"2006","journal-title":"Blood"},{"issue":"10","key":"ppat.1013180.ref049","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0003321","article-title":"Cerebrospinal fluid dendritic cells infiltrate the brain parenchyma and target the cervical lymph nodes under neuroinflammatory conditions","volume":"3","author":"E Hatterer","year":"2008","journal-title":"PLoS One"},{"issue":"3","key":"ppat.1013180.ref050","doi-asserted-by":"crossref","first-page":"164","DOI":"10.4161\/cam.20281","article-title":"Migration of monocytes after intracerebral injection","volume":"6","author":"M Kaminski","year":"2012","journal-title":"Cell Adh Migr"},{"issue":"6","key":"ppat.1013180.ref051","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1111\/j.1365-2990.1993.tb00476.x","article-title":"CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance","volume":"19","author":"S Kida","year":"1993","journal-title":"Neuropathol Appl Neurobiol"},{"key":"ppat.1013180.ref052","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-1-4939-8709-2_3","article-title":"Meningeal Immunity, Drainage, and Tertiary Lymphoid Structure Formation","volume":"1845","author":"A Louveau","year":"2018","journal-title":"Methods Mol Biol"},{"issue":"4","key":"ppat.1013180.ref053","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1113\/jphysiol.1965.sp007797","article-title":"A flow of cerebrospinal fluid along the central canal of the spinal cord of the rabbit and communications between this canal and the sacral subarachnoid space","volume":"181","author":"MW Bradbury","year":"1965","journal-title":"J Physiol"},{"issue":"36","key":"ppat.1013180.ref054","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.adn3259","article-title":"Cerebrospinal fluid flow extends to peripheral nerves further unifying the nervous system","volume":"10","author":"AP Ligocki","year":"2024","journal-title":"Sci Adv"},{"key":"ppat.1013180.ref055","article-title":"Simian Immunodeficiency Virus-Infected Macrophage Traffic Out of the Central Nervous System","author":"X Alvarez","year":"2025","journal-title":"Res Sq"},{"issue":"5","key":"ppat.1013180.ref056","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1002\/cyto.a.20859","article-title":"Evaluation of a 12-color flow cytometry panel to study lymphocyte, monocyte, and dendritic cell subsets in humans","volume":"77","author":"P Autissier","year":"2010","journal-title":"Cytometry A"},{"key":"ppat.1013180.ref057","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.jim.2010.06.017","article-title":"Immunophenotyping of lymphocyte, monocyte and dendritic cell subsets in normal rhesus macaques by 12-color flow cytometry: clarification on DC heterogeneity","volume":"360","author":"P Autissier","year":"2010","journal-title":"J Immunol Methods"},{"issue":"12","key":"ppat.1013180.ref058","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1021\/acs.molpharmaceut.1c00698","article-title":"Phagocytic Uptake of Polymeric Particles by Immune Cells under Flow Conditions","volume":"18","author":"M Srinivas","year":"2021","journal-title":"Mol Pharm"},{"issue":"4","key":"ppat.1013180.ref059","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/0142-9612(88)90033-6","article-title":"Effect of the size and surface charge of polymer microspheres on their phagocytosis by macrophage","volume":"9","author":"Y Tabata","year":"1988","journal-title":"Biomaterials"},{"key":"ppat.1013180.ref060","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1146\/annurev-immunol-102319-103410","article-title":"Meningeal Immunity and Its Function in Maintenance of the Central Nervous System in Health and Disease","volume":"38","author":"K Alves de Lima","year":"2020","journal-title":"Annu Rev Immunol"},{"issue":"9","key":"ppat.1013180.ref061","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/s41583-019-0201-x","article-title":"Macrophages at CNS interfaces: ontogeny and function in health and disease","volume":"20","author":"K Kierdorf","journal-title":"Nat Rev Neurosci"},{"issue":"2","key":"ppat.1013180.ref062","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/j.1365-2990.2007.00926.x","article-title":"Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology","volume":"34","author":"RO Carare","year":"2008","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"1","key":"ppat.1013180.ref063","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s12975-010-0049-x","article-title":"High and Low Molecular Weight Fluorescein Isothiocyanate (FITC)-Dextrans to Assess Blood-Brain Barrier Disruption: Technical Considerations","volume":"2","author":"A Hoffmann","year":"2011","journal-title":"Transl Stroke Res"},{"issue":"1","key":"ppat.1013180.ref064","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1046\/j.0305-1846.2003.00512.x","article-title":"Trafficking of superparamagnetic iron oxide particles (Combidex) from brain to lymph nodes in the rat","volume":"30","author":"LL Muldoon","year":"2004","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"1","key":"ppat.1013180.ref065","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/s41420-023-01490-2","article-title":"Recent progress in the effect of magnetic iron oxide nanoparticles on cells and extracellular vesicles","volume":"9","author":"Y Chen","year":"2023","journal-title":"Cell Death Discov"},{"issue":"6","key":"ppat.1013180.ref066","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1002\/mrm.22765","article-title":"Magnetic poly(lactide-co-glycolide) and cellulose particles for MRI-based cell tracking","volume":"65","author":"MK Nkansah","year":"2011","journal-title":"Magn Reson Med"},{"issue":"1","key":"ppat.1013180.ref067","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s12951-020-0580-1","article-title":"Size-isolation of superparamagnetic iron oxide nanoparticles improves MRI, MPI and hyperthermia performance","volume":"18","author":"SM Dadfar","year":"2020","journal-title":"J Nanobiotechnology"},{"issue":"4","key":"ppat.1013180.ref068","doi-asserted-by":"crossref","first-page":"617","DOI":"10.3390\/ma12040617","article-title":"Superparamagnetic Iron Oxide Nanoparticles-Current and Prospective Medical Applications","volume":"12","author":"J Duli\u0144ska-Litewka","year":"2019","journal-title":"Materials (Basel)"},{"key":"ppat.1013180.ref069","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3389\/fonc.2019.00059","article-title":"Functionalized Superparamagnetic Iron Oxide Nanoparticles (SPIONs) as Platform for the Targeted Multimodal Tumor Therapy","volume":"9","author":"C Janko","year":"2019","journal-title":"Front Oncol"},{"issue":"1","key":"ppat.1013180.ref070","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41420-024-02037-9","article-title":"Ferroptosis: A double-edged sword","volume":"10","author":"S Wang","year":"2024","journal-title":"Cell Death Discov"},{"issue":"4","key":"ppat.1013180.ref071","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1189\/jlb.0306176","article-title":"T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa","volume":"80","author":"J Goldmann","year":"2006","journal-title":"J Leukoc Biol"},{"issue":"4","key":"ppat.1013180.ref072","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1000842","article-title":"Increased monocyte turnover from bone marrow correlates with severity of SIV encephalitis and CD163 levels in plasma","volume":"6","author":"TH Burdo","year":"2010","journal-title":"PLoS Pathog"},{"issue":"14","key":"ppat.1013180.ref073","doi-asserted-by":"crossref","first-page":"2917","DOI":"10.1182\/blood-2009-02-204263","article-title":"The level of monocyte turnover predicts disease progression in the macaque model of AIDS","volume":"114","author":"A Hasegawa","year":"2009","journal-title":"Blood"},{"issue":"7717","key":"ppat.1013180.ref074","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s41586-018-0368-8","article-title":"Functional aspects of meningeal lymphatics in ageing and Alzheimer\u2019s disease","volume":"560","author":"S Da Mesquita","year":"2018","journal-title":"Nature"},{"issue":"10","key":"ppat.1013180.ref075","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1038\/s41593-018-0227-9","article-title":"CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature","volume":"21","author":"A Louveau","year":"2018","journal-title":"Nat Neurosci"},{"key":"ppat.1013180.ref076","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.29738","article-title":"Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI","volume":"6","author":"M Absinta","year":"2017","journal-title":"Elife"},{"issue":"7767","key":"ppat.1013180.ref077","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41586-019-1419-5","article-title":"Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid","volume":"572","author":"JH Ahn","year":"2019","journal-title":"Nature"},{"issue":"1","key":"ppat.1013180.ref078","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12987-017-0063-4","article-title":"Barrier dysfunction or drainage reduction: differentiating causes of CSF protein increase","volume":"14","author":"M Asgari","year":"2017","journal-title":"Fluids Barriers CNS"},{"issue":"7","key":"ppat.1013180.ref079","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1084\/jem.20142290","article-title":"A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules","volume":"212","author":"A Aspelund","year":"2015","journal-title":"J Exp Med"},{"issue":"2","key":"ppat.1013180.ref080","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s00234-014-1461-9","article-title":"Pathways of cerebrospinal fluid outflow: a deeper understanding of resorption","volume":"57","author":"L Chen","year":"2015","journal-title":"Neuroradiology"},{"issue":"5","key":"ppat.1013180.ref081","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.neuron.2016.08.027","article-title":"Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer\u2019s Disease?","volume":"91","author":"A Louveau","year":"2016","journal-title":"Neuron"},{"issue":"10","key":"ppat.1013180.ref082","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.it.2015.08.006","article-title":"Revisiting the Mechanisms of CNS Immune Privilege","volume":"36","author":"A Louveau","year":"2015","journal-title":"Trends Immunol"},{"issue":"9","key":"ppat.1013180.ref083","doi-asserted-by":"crossref","first-page":"3210","DOI":"10.1172\/JCI90603","article-title":"Understanding the functions and relationships of the glymphatic system and meningeal lymphatics","volume":"127","author":"A Louveau","year":"2017","journal-title":"J Clin Invest"},{"issue":"1","key":"ppat.1013180.ref084","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1038\/s41467-017-01484-6","article-title":"Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice","volume":"8","author":"Q Ma","year":"2017","journal-title":"Nat Commun"},{"issue":"2","key":"ppat.1013180.ref085","doi-asserted-by":"crossref","first-page":"286","DOI":"10.4049\/jimmunol.1900838","article-title":"Meningeal Lymphatics: From Anatomy to Central Nervous System Immune Surveillance","volume":"204","author":"Z Papadopoulos","year":"2020","journal-title":"J Immunol"},{"issue":"9","key":"ppat.1013180.ref086","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.tins.2016.07.001","article-title":"How Do Meningeal Lymphatic Vessels Drain the CNS?","volume":"39","author":"D Raper","year":"2016","journal-title":"Trends Neurosci"},{"issue":"7","key":"ppat.1013180.ref087","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1007\/s00221-017-4956-x","article-title":"Indications for cellular migration from the central nervous system to its draining lymph nodes in CD11c-GFP+ bone-marrow chimeras following EAE","volume":"235","author":"F Schiefenh\u00f6vel","year":"2017","journal-title":"Exp Brain Res"},{"key":"ppat.1013180.ref088","doi-asserted-by":"crossref","first-page":"1233908","DOI":"10.3389\/fimmu.2023.1233908","article-title":"Immune cells as messengers from the CNS to the periphery: the role of the meningeal lymphatic system in immune cell migration from the CNS","volume":"14","author":"C Laaker","year":"2023","journal-title":"Front Immunol"},{"key":"ppat.1013180.ref089","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/2045-8118-11-12","article-title":"Cerebrospinal fluid is drained primarily via the spinal canal and olfactory route in young and aged spontaneously hypertensive rats","volume":"11","author":"LA Murtha","year":"2014","journal-title":"Fluids Barriers CNS"},{"issue":"8002","key":"ppat.1013180.ref090","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41586-023-06993-7","article-title":"Identification of direct connections between the dura and the brain","volume":"627","author":"LCD Smyth","year":"2024","journal-title":"Nature"},{"issue":"1","key":"ppat.1013180.ref091","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1743-8454-1-2","article-title":"Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species","volume":"1","author":"M Johnston","year":"2004","journal-title":"Cerebrospinal Fluid Res"},{"issue":"4","key":"ppat.1013180.ref092","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/j.1365-2990.2006.00737.x","article-title":"The olfactory route for cerebrospinal fluid drainage into the peripheral lymphatic system","volume":"32","author":"BA Walter","year":"2006","journal-title":"Neuropathol Appl Neurobiol"},{"key":"ppat.1013180.ref093","article-title":"Spinal arachnoid granulations with special reference to the cerebrospinal fluid","author":"R Elman","year":"1923","journal-title":"Johns Hopkins Hospital Bulletin"},{"issue":"5","key":"ppat.1013180.ref094","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/BF00328377","article-title":"Human spinal arachnoid villi and granulations","volume":"11","author":"DK Kido","year":"1976","journal-title":"Neuroradiology"},{"key":"ppat.1013180.ref095","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/ar.1091450107","article-title":"The spinal arachnoid villi of the monkeys Cercopithecus aethiops sabaeus and Macaca irus","volume":"145","author":"K WELCH","year":"1963","journal-title":"Anat Rec"},{"key":"ppat.1013180.ref096","first-page":"153","article-title":"The connexions of the spinal sub-arachnoid space with the lymphatic system","volume":"82","author":"JB Brierley","year":"1948","journal-title":"J Anat"},{"issue":"1","key":"ppat.1013180.ref097","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF02658191","article-title":"\u00dcber die Abflu\u00dfwege aus den submeningealen R\u00e4umen des R\u00fcckenmarks","volume":"58","author":"G Iwanow","year":"1928","journal-title":"Z Ges Exp Med"},{"issue":"12","key":"ppat.1013180.ref098","doi-asserted-by":"crossref","first-page":"3645","DOI":"10.1084\/jem.20170391","article-title":"Development and plasticity of meningeal lymphatic vessels","volume":"214","author":"S Antila","year":"2017","journal-title":"J Exp Med"},{"issue":"3","key":"ppat.1013180.ref099","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/BF00239012","article-title":"Morphological indications for considerable diffuse reabsorption of cerebrospinal fluid in spinal meninges particularly in the areas of meningeal funnels. An electronmicroscopical study including tracing experiments in rats","volume":"189","author":"W Zenker","year":"1994","journal-title":"Anat Embryol (Berl)"},{"issue":"14","key":"ppat.1013180.ref100","doi-asserted-by":"crossref","first-page":"8389","DOI":"10.1073\/pnas.1433000100","article-title":"Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin","volume":"100","author":"P Kivis\u00e4kk","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1013180.ref101","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S0046-8177(98)90395-1","article-title":"HLA-DR-positive dendritic cells of the normal human choroid plexus: a potential reservoir of HIV in the central nervous system","volume":"29","author":"A Hanly","year":"1998","journal-title":"Hum Pathol"},{"key":"ppat.1013180.ref102","doi-asserted-by":"crossref","first-page":"1240946","DOI":"10.3389\/fimmu.2023.1240946","article-title":"Simian immunodeficiency virus-infected rhesus macaques with AIDS co-develop cardiovascular pathology and encephalitis","volume":"14","author":"KS White","year":"2023","journal-title":"Front Immunol"},{"issue":"7348","key":"ppat.1013180.ref103","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nature10003","article-title":"Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine","volume":"473","author":"SG Hansen","year":"2011","journal-title":"Nature"},{"issue":"7469","key":"ppat.1013180.ref104","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nature12519","article-title":"Immune clearance of highly pathogenic SIV infection","volume":"502","author":"SG Hansen","year":"2013","journal-title":"Nature"},{"issue":"21","key":"ppat.1013180.ref105","doi-asserted-by":"crossref","first-page":"10187","DOI":"10.1128\/JVI.75.21.10187-10199.2001","article-title":"Role of CD8(+) lymphocytes in control of simian immunodeficiency virus infection and resistance to rechallenge after transient early antiretroviral treatment","volume":"75","author":"JD Lifson","year":"2001","journal-title":"J Virol"},{"issue":"1","key":"ppat.1013180.ref106","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s11481-018-9809-2","article-title":"Macrophages but not Astrocytes Harbor HIV DNA in the Brains of HIV-1-Infected Aviremic Individuals on Suppressive Antiretroviral Therapy","volume":"14","author":"A Ko","year":"2019","journal-title":"J Neuroimmune Pharmacol"},{"issue":"4","key":"ppat.1013180.ref107","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1021\/acssynbio.6b00373","article-title":"Controlling Multicycle Replication of Live-Attenuated HIV-1 Using an Unnatural Genetic Switch","volume":"6","author":"Z Yuan","year":"2017","journal-title":"ACS Synth Biol"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1013180","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013180","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T19:09:15Z","timestamp":1764875355000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013180"}},"subtitle":[],"editor":[{"given":"David T.","family":"Evans","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,1]]},"references-count":107,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1013180","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,1]]}}}