title: Soluble TLR2 and 4 concentrations in cerebrospinal fluid in HIV/SIV-related neuropathological conditions.
abstract: HIV in the central nervous system (CNS) mainly infects microglial cells which are known to express toll-like receptors (TLRs). This paper aimed to study the role of soluble TLR2 (sTLR2), sTLR4, and other inflammatory markers in cerebrospinal fluid (CSF) in HIV/Simian immunodeficiency virus (SIV)-related neurological sequelae. We determined sTLR2 and sTLR4 levels in CSF and serum/plasma of SIV-infected rhesus macaques with and without neurological sequelae, as well as in HIV-infected patients with and without cognitive impairments and Alzheimer's disease (AD) patients and matched controls. CSF cytokines and chemokines levels were analyzed in macaques as markers of neuroinflammation, while neopterin and S100B CSF concentrations were measured in HIV-infected patients as microglial and astrocyte marker, respectively. We found detectable levels of sTLR2 and sTLR4 in CSF of macaques and humans. Furthermore, CSF sTLR2 and sTLR4 concentrations were higher in SIV-infected macaques with neurological sequelae compared to those without neurological complications (p = 0.0003 and p = 0.0006, respectively). CSF IL-8 and monocyte chemoattractant protein-1 (MCP-1) levels were elevated in macaques with neurological sequelae, and a positive correlation was found between CSF levels of sTLR2/4 and IL-8 and MCP-1. Also in humans, elevated CSF sTLR4 levels were found in HIV-infected patients with cognitive impairments compared to HIV-infected patients with normal cognition (p = 0.019). Unlike CSF S100B levels, neopterin correlated positively with sTLR2 and sTLR4. No difference was found in plasma and CSF sTLR2 and sTLR4 levels between AD patients and control subjects (p = 0.26). In conclusion, CSF sTLR2 and sTLR4 may play a role in HIV/SIV-related neuroinflammation and subsequent neuropathology.
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Health Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. kmothapo@gmail.com.
authors.forename: Khutso M
authors.initials: KM
authors.lastname: Mothapo
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Health Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Ten Oever
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Health Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Koopmans
authors.affiliation: Department of Medical Microbiology-Section Virology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: F F
authors.initials: FF
authors.lastname: Stelma
authors.affiliation: Alternatives Unit, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Burm
authors.affiliation: Alternatives Unit, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Bajramovic
authors.affiliation: Departments of Neurology and Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: Verbeek
authors.affiliation: Radboudumc Alzheimer Centre, Department of Geriatric Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M G Olde
authors.initials: MGO
authors.lastname: Rikkert
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Health Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: M G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Koopman
authors.affiliation: Department of Internal Medicine and Nijmegen Institute for Health Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: van der Ven
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid* / Q000150:complications / Q000821:virology; D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D060825:Cognitive Dysfunction / Q000097:blood / Q000134:cerebrospinal fluid* / Q000150:complications / Q000821:virology; D005260:Female; D015870:Gene Expression; D006678:HIV / Q000276:immunology / Q000472:pathogenicity; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid* / Q000150:complications / Q000821:virology; D006801:Humans; D016209:Interleukin-8 / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D017628:Microglia / Q000276:immunology / Q000473:pathology / Q000821:virology; D008875:Middle Aged; D019798:Neopterin / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D064568:S100 Calcium Binding Protein beta Subunit / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000134:cerebrospinal fluid* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000472:pathogenicity; D012995:Solubility; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
chemical_list: D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016209:Interleukin-8; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D019798:Neopterin
keywords: HAND; HIV neuroinflammation; Pro-inflammation; SIV neuroinflammation; sTLR2; sTLR4