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Plasma (1 → 3)-β-d-glucan and suPAR levels correlate with neurocognitive performance in people living with HIV on antiretroviral therapy: a CHARTER analysis

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Abstract

Despite antiretroviral therapy (ART), people living with HIV (PLWH) have higher rates of non-AIDS disorders, such as neurocognitive (NC) impairment (NCI) than the general population. (1-3)-β-d-Glucan (BDG) is a fungal cell wall component which serves as a biomarker for gut barrier integrity failure and microbial and fungal translocation. The primary objective of this study was to determine whether higher plasma and cerebrospinal fluid (CSF) levels of BDG and suPAR were associated with NCI in PLWH. Paired blood and CSF samples were collected cross-sectionally from 61 male adult PLWH on ART (95% virally suppressed) who underwent a detailed NC assessment as part of the prospective CHARTER study between 2005 and 2015. BDG and soluble urokinase plasminogen activator receptor (suPAR) were measured in frozen blood and CSF samples while soluble CD14 (sCD14), intestinal fatty acid binding protein (IFABP), and CD4/CD8 ratio were measured in blood only. Spearman’s rho correlation analysis assessed associations between BDG, other biomarkers, and NC performance. Median BDG levels were 18 pg/mL in plasma (range 2–60 pg/mL) and 20 pg/mL in CSF (range 0–830 pg/mL). Higher levels of plasma BDG were associated with worse NC performance (Spearman’s rho = − 0.32; p = 0.013) and with the presence of NCI (p = 0.027). A plasma BDG cutoff of > 30 pg/mL was 30% sensitive and 100% specific for NCI. After adjusting for age, higher plasma suPAR levels were also associated with worse NC performance (p < 0.01). No significant associations were observed between the remaining biomarkers and the NC variables. Plasma levels of BDG and age-adjusted suPAR may be new biomarkers for the detection of NCI in PLWH on suppressive ART.

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References

  • Ancuta P, Kamat A, Kunstman KJ, Kim EY, Autissier P, Wurcel A, Zaman T, Stone D, Mefford M, Morgello S, Singer EJ, Wolinsky SM, Gabuzda D (2008) Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One 3:e2516

    Article  Google Scholar 

  • Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69(18):1789–1799

    Article  CAS  Google Scholar 

  • Blackstone K, Moore DJ, Franklin DR, Clifford DB, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, Ellis RJ, Atkinson JH, Grant I, Heaton RK (2012) Defining neurocognitive impairment in HIV: deficit scores versus clinical ratings. Clin Neuropsychol 26(6):894–908

    Article  CAS  Google Scholar 

  • Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I, Heaton RK, HNRC Group (2004) Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. J Clin Exp Neuropsychol 26:307–319

    Article  Google Scholar 

  • Cinque P, Nebuloni M, Santovito ML, Price RW, Gisslen M, Hagberg L, Bestetti A, Vago G, Lazzarin A, Blasi F, Sidenius N (2004) The urokinase receptor is overexpressed in the AIDS dementia complex and other neurological manifestations. Ann Neurol 55(5):687–694

    Article  CAS  Google Scholar 

  • Deeks SG, Verdin E, McCune JM (2012) Immunosenescence and HIV. Curr Opin Immunol 24(4):501–506

    Article  CAS  Google Scholar 

  • Dinan TG, Stilling RM, Stanton C, Cryan JF (2015) Collective unconscious: how gut microbes shape human behavior. J Psychiatr Res 63:1–9

    Article  Google Scholar 

  • Farhour Z, Mehraj V, Chen J, Ramendra R, Lu H, Routy JP (2018) Use of (1-->3)-beta-d-glucan for diagnosis and management of invasive mycoses in HIV-infected patients. Mycoses 61:718–722

    Article  CAS  Google Scholar 

  • Gonzalez R, Heaton RK, Moore DJ, Letendre S, Ellis RJ, Wolfson T et al (2003) Computerized reaction time battery versus a traditional neuropsychological battery: detecting HIV-related impairments. J Int Neuropsychol Soc 9(1):64–71

    Article  Google Scholar 

  • Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75(23):2087–2096

    Article  CAS  Google Scholar 

  • Heldt S, Prattes J, Eigl S, Spiess B, Flick H, Rabensteiner J et al (2018) Diagnosis of invasive aspergillosis in hematological malignancy patients: performance of cytokines, Asp LFD, and Aspergillus PCR in same day blood and bronchoalveolar lavage samples. J Infect 77(3):235–241

    Article  Google Scholar 

  • Hodges GW, Bang CN, Wachtell K, Eugen-Olsen J, Jeppesen JL (2015) suPAR: a new biomarker for cardiovascular disease? Can J Cardiol 31(10):1293–1302

    Article  Google Scholar 

  • Hoenigl M (2019) Fungal translocation: a driving force behind the occurrence of non-AIDS events? Clin Infect Dis. https://doi.org/10.1093/cid/ciz215

  • Hoenigl M, Raggam RB, Wagner J, Valentin T, Leitner E, Seeber K, Zollner-Schwetz I, Krammer W, Prüller F, Grisold AJ, Krause R (2013) Diagnostic accuracy of soluble urokinase plasminogen activator receptor (suPAR) for prediction of bacteremia in patients with systemic inflammatory response syndrome. Clin Biochem 46(3):225–229

    Article  CAS  Google Scholar 

  • Hoenigl M, Perez-Santiago J, Nakazawa M, Faria de Oliveira M, Zhang Y, Finkelman M et al (2016a) (1 → 3)-β-glucan: a biomarker for microbial translocation in individuals with acute or early HIV infection? Front Immunol 7:404

  • Hoenigl M, de Oliveira MF, Perez-Santiago J, Zhang Y, Morris S, McCutchan AJ et al (2016b) (1 → 3)-beta-d-Glucan levels correlate with neurocognitive functioning in HIV-infected persons on suppressive antiretroviral therapy: a cohort study. Medicine (Baltimore) 95(11):e3162

    Article  CAS  Google Scholar 

  • Hoenigl M, Moser C, Funderburg N, Bosch R, Kantor A, Zhang Y et al (2018) Soluble urokinase plasminogen activator receptor (suPAR) is predictive of non-AIDS events during antiretroviral therapy-mediated viral suppression. Clin Infect Dis. https://doi.org/10.1093/cid/ciy966

    Article  Google Scholar 

  • Hunt PW (2012) HIV and inflammation: mechanisms and consequences. Curr HIV/AIDS Rep 9(2):139–147

    Article  Google Scholar 

  • Kamat A, Lyons JL, Misra V, Uno H, Morgello S, Singer EJ, Gabuzda D (2012) Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection. J Acquir Immune Defic Syndr 60:234–243

    Article  CAS  Google Scholar 

  • Lawn SD, Myer L, Bangani N, Vogt M, Wood R (2007) Plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) and early mortality risk among patients enrolling for antiretroviral treatment in South Africa. BMC Infect Dis 7:41

    Article  Google Scholar 

  • Lozupone CA, Li M, Campbell TB, Flores SC, Linderman D, Gebert MJ, Knight R, Fontenot AP, Palmer BE (2013) Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe 14(3):329–339

    Article  CAS  Google Scholar 

  • Lyons JL, Uno H, Ancuta P, Kamat A, Moore DJ, Singer EJ, Morgello S, Gabuzda D (2011) Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection. J Acquir Immune Defic Syndr 57(5):371–379

    Article  CAS  Google Scholar 

  • McLaurin KA, Booze RM, Mactutus CF (2019) Diagnostic and prognostic biomarkers for HAND. J Neurovirol

  • Mehraj V, Ramendra R, Isnard S, Dupuy FP, Ponte R, Chen J, Kema I, Jenabian MA, Costinuik CT, Lebouché B, Thomas R, Coté P, Leblanc R, Baril JG, Durand M, Chartrand-Lefebvre C, Tremblay C, Ancuta P, Bernard NF, Sheppard DC, Routy JP, Montreal Primary HIV Infection Study and Canadian HIV and Aging Cohort Study Groups, Milne C, Lavoie S, Friedman J, Duchastel M, Villielm F, Asselin F, Boissonnault M, Maziade PJ, Lavoie S, Milne M, Miaki NZ, Thériault ME, Lessard B, Charron MA, Dufresne S, Turgeon ME, Vézina S, Huchet E, Kerba JP, Poliquin M, Poulin S, Rochette P, Junod P, Longpré D, Pilarski R, Sasseville E, Charest L, Hamel A, Cloutier-Blais A, Massoud S, Chano F, Trottier B, Labrecque L, Fortin C, Hal-Gagne V, Munoz M, Deligne B, Martel-Laferrière V, Trottier B, Goyer ME, Teltscher M, de Pokomandy A, Cox J, Beauchamp E, Haraoui LP (2019) Circulating (1-->3)-beta-D-Glucan is associated with immune activation during HIV infection. Clin Infect Dis

  • Morris A, Hillenbrand M, Finkelman M, George MP, Singh V, Kessinger C, Lucht L, Busch M, McMahon D, Weinman R, Steele C, Norris KA, Gingo MR (2012) Serum (1-->3)-beta-D-glucan levels in HIV-infected individuals are associated with immunosuppression, inflammation, and cardiopulmonary function. J Acquir Immune Defic Syndr 61(4):462–468

    Article  CAS  Google Scholar 

  • Odabasi Z, Mattiuzzi G, Estey E, Kantarjian H, Saeki F, Ridge RJ, Ketchum PA, Finkelman MA, Rex JH, Ostrosky-Zeichner L (2004) Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 39(2):199–205

    Article  CAS  Google Scholar 

  • Oliveira I, Andersen A, Furtado A, Medina C, da Silva D, da Silva ZJ, et al (2012) Assessment of simple risk markers for early mortality among HIV-infected patients in Guinea-Bissau: a cohort study. BMJ Open 2(6).https://doi.org/10.1136/bmjopen-2012-001587. Print 2012

    Article  Google Scholar 

  • Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT et al (2006) Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 43(1):27–34

    Article  CAS  Google Scholar 

  • Perez-Santiago J, Gianella S, Massanella M, Spina CA, Karris MY, Var SR et al (2013) Gut Lactobacillales are associated with higher CD4 and less microbial translocation during HIV infection. AIDS 27(12):1921–1931

    Article  CAS  Google Scholar 

  • Petra AI, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, Theoharides TC (2015) Gut-microbiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation. Clin Ther 37(5):984–995

    Article  CAS  Google Scholar 

  • Prattes J, Hoenigl M, Rabensteiner J, Raggam RB, Prueller F, Zollner-Schwetz I, Valentin T, Hönigl K, Fruhwald S, Krause R (2014) Serum 1,3-beta-d-glucan for antifungal treatment stratification at the intensive care unit and the influence of surgery. Mycoses 57(11):679–686

    Article  CAS  Google Scholar 

  • Pruller F, Wagner J, Raggam RB, Hoenigl M, Kessler HH, Truschnig-Wilders M, Krause R (2014) Automation of serum (1-->3)-beta-D-glucan testing allows reliable and rapid discrimination of patients with and without candidemia. Med Mycol 52(5):455–461

    Article  Google Scholar 

  • Raggam RB, Wagner J, Pruller F, Grisold A, Leitner E, Zollner-Schwetz I et al (2014) Soluble urokinase plasminogen activator receptor predicts mortality in patients with systemic inflammatory response syndrome. J Intern Med 276:651–658

    Article  CAS  Google Scholar 

  • Ramendra R, Isnard S, Mehraj V, Chen J, Zhang Y, Finkelman M, Routy JP (2019) Circulating LPS and (1-->3)-beta-D-glucan: a Folie a Deux contributing to HIV-associated immune activation. Front Immunol 10:465

    Article  CAS  Google Scholar 

  • Rasmussen LJ, Knudsen A, Katzenstein TL, Gerstoft J, Obel N, Jorgensen NR et al (2016) Soluble urokinase plasminogen activator receptor (suPAR) is a novel, independent predictive marker of myocardial infarction in HIV-1-infected patients: a nested case-control study. HIV Med 17(5):350–357

    Article  CAS  Google Scholar 

  • Reischies FM, Prattes J, Pruller F, Eigl S, List A, Wolfler A et al (2016) Prognostic potential of 1,3-beta-d-glucan levels in bronchoalveolar lavage fluid samples. J Infect 72(1):29–35

    Article  Google Scholar 

  • Sidenius N, Nebuloni M, Sala S, Zerbi P, Price RW, Gisslen M, Hagberg L, Vago L, Lazzarin A, Blasi F, Cinque P (2004) Expression of the urokinase plasminogen activator and its receptor in HIV-1-associated central nervous system disease. J Neuroimmunol 157(1–2):133–139

    Article  CAS  Google Scholar 

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Funding

This work was supported by funds from the following: HNRP developmental grant PST-HN68 (from parent NIMH grant MH062512), and grants from the National Institutes of Health: AI036214, DA026306, AI064086, MH081482, MH113477, K24 MH097673 and AI106039. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript N01MH022005, HHSN271201000036C, R01MH107345 K23DA037793 R01 DA 034362.

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Author notes

  1. Martin Hoenigl

    Present address: Division of Infectious Diseases & Global Public Health, University of California San Diego, San Diego, CA, USA

Authors and Affiliations

  1. Division of Infectious Diseases & Global Public Health, University of California San Diego, San Diego, CA, USA

    Sara Gianella, Scott L. Letendre, Thaidra Gaufin, Magali Porrachia & Milenka Vargas-Meneses

  2. Department of Medicine, University of California San Diego, San Diego, CA, USA

    Scott L. Letendre

  3. Department of Psychiatry, University of California San Diego, San Diego, CA, USA

    Scott L. Letendre, Jennifer Iudicello, Donald Franklin & Ronald J. Ellis

  4. Research Laboratory, Associates of Cape Cod, Inc., Falmouth, MA, USA

    Yonglong Zhang & Malcolm Finkelman

  5. Department of Neurosciences, HIV Neurobehavioral Research Center, University of California, San Diego, CA, USA

    Ronald J. Ellis

  6. Section of Infectious Diseases and Tropical Medicine, Medical University of Graz, Graz, Austria

    Martin Hoenigl

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  1. Sara Gianella
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Corresponding author

Correspondence to Sara Gianella.

Ethics declarations

The UCSD Human Research Protections Program approved the study protocol, consent, and all study-related procedures. All study participants provided voluntary, written informed consent before any study procedures were undertaken.

Conflict of interest

MH received grant funding from Gilead. YZ and MF are employees of Associates of Cape Cod. All other authors declare no conflict of interest.

Off-label use

Fungitell®, the FDA-cleared IVD kit used for the measurement of (1 → 3)-β-glucan in serum, does not have an indication for the diagnostic use of BG titers in CSF. The data presented here represents the research use only.

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Gianella, S., Letendre, S.L., Iudicello, J. et al. Plasma (1 → 3)-β-d-glucan and suPAR levels correlate with neurocognitive performance in people living with HIV on antiretroviral therapy: a CHARTER analysis. J. Neurovirol. 25, 837–843 (2019). https://doi.org/10.1007/s13365-019-00775-6

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