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The Association of Immune Markers with Cognitive Performance in South African HIV-Positive Patients

  • Monray E. WilliamsEmail author
  • Jonathan C. Ipser
  • Dan J. Stein
  • John A. Joska
  • Petrus J. W. Naudé
ORIGINAL ARTICLE

Abstract

Dysregulated expression of neuro-immune markers has previously been linked to HIV-associated neurocognitive impairment. We undertook an exploratory approach in a HIV clade-C cohort, investigating the association between eight immune markers and neurocognitive performance in 99 HIV+ and 51 HIV- participants. Markers were selected on preliminary and putative evidence of their link to key neuro-immune functions. Cognitive performance was established using a battery of tests sensitive to HIV-associated neurocognitive impairment, with domain-based scores utilized in analysis. The markers Thymidine phosphorylase (TYMP) and Neutrophil gelatinase-associated lipocalin (NGAL) were significantly higher while Matrix Metalloproteinase (MMP)9 was significantly lower in HIV+ participants. Our results further showed that in the HIV+ group, worse psychomotor processing speed was associated with higher TYMP and NGAL levels and worse motor function was associated with higher NGAL levels. Future studies should explore the underlying mechanisms of these markers in HIV-associated neurocognitive impairment.

Graphical Abstract

The association of peripheral immune markers with neurocognitive performance in South African HIV-positive patients.

Keywords

HIV HIV-associated neurocognitive impairments HAND Cognition Neuroinflammation and cytokines 

Notes

Acknowledgements

The authors would like to acknowledge all funding contributors. MW was funded by the National Research Foundation (NRF) and Poliomyelitis Research Foundation (PRF). PN was funded by the Harry Crossley Foundation and South African Society for Biological Psychiatry.

Compliance with Ethical Standards

Conflict of Interest

None.

Supplementary material

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References

  1. Abassi M, Morawski BM, Nakigozi G, Nakasujja N, Kong X, Meya DB, Robertson K, Gray R, Wawer MJ, Sacktor N, Boulware DR (2017) Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda. J Neuro-Oncol 23:369–375.  https://doi.org/10.1007/s13365-016-0505-9 Google Scholar
  2. Acevedo A, Loewenstein DA, Barker WW et al (2000) Category fluency test: normative data for English- and Spanish-speaking elderly. J Int Neuropsychol Soc 6:760–769CrossRefGoogle Scholar
  3. Al Nimer F, Elliott C, Bergman J et al (2016) Lipocalin-2 is increased in progressive multiple sclerosis and inhibits remyelination. Neurol Neuroimmunol Neuroinflamm 3:e191.  https://doi.org/10.1212/NXI.0000000000000191 CrossRefGoogle Scholar
  4. Banks WA, Ercal N, Price TO (2006) The blood-brain barrier in neuroAIDS. Curr HIV Res 4:259–266.  https://doi.org/10.1016/j.ncl.2006.03.009 CrossRefGoogle Scholar
  5. Beck SE, Queen SE, Witwer KW, Metcalf Pate KA, Mangus LM, Gama L, Adams RJ, Clements JE, Christine Zink M, Mankowski JL (2015) Paving the path to HIV neurotherapy: predicting SIV CNS disease. Eur J Pharmacol 759:303–312.  https://doi.org/10.1016/j.ejphar.2015.03.018 CrossRefGoogle Scholar
  6. Bell JE (2004) An update on the neuropathology of HIV in the HAART era’, Histopathology.  https://doi.org/10.1111/j.1365-2559.2004.02004.x
  7. Benedict RHB, Schretlen D, Groninger L, Brandt J (1998) Hopkins verbal learning test ? Revised: normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychol (Neuropsychology, Dev Cogn Sect D) 12:43–55.  https://doi.org/10.1076/clin.12.1.43.1726 Google Scholar
  8. Bi F, Huang C, Tong J, Qiu G, Huang B, Wu Q, Li F, Xu Z, Bowser R, Xia XG, Zhou H (2013) Reactive astrocytes secrete lcn2 to promote neuron death. Proc Natl Acad Sci U S A 110:4069–4074.  https://doi.org/10.1073/pnas.1218497110 CrossRefGoogle Scholar
  9. Bowers NL, Helton ES, Huijbregts RPH, Goepfert PA, Heath SL, Hel Z (2014) Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway. PLoS Pathog 10:e1003993.  https://doi.org/10.1371/journal.ppat.1003993 CrossRefGoogle Scholar
  10. Brabers NACH, Nottet HSLM (2006) Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIV-associated dementia. Eur J Clin Investig 36:447–458.  https://doi.org/10.1111/j.1365-2362.2006.01657.x CrossRefGoogle Scholar
  11. Burdo TH, Weiffenbach A, Woods SP, Letendre S, Ellis RJ, Williams KC (2013) Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection. AIDS 27:1387–1395.  https://doi.org/10.1097/QAD.0b013e32836010bd CrossRefGoogle Scholar
  12. Butters N, Grant I, Haxyb J, Judd LL, Martin A, McClelland J, Pequegnat W, Schacter D, Stover E (1990) Assessment of Aids-related cognitive changes: recommendations of the NIMH workshop on neuropsychological assessment approaches. J Clin Exp Neuropsychol 12:963–978.  https://doi.org/10.1080/01688639008401035 CrossRefGoogle Scholar
  13. Chapouly C, Tadesse Argaw A, Horng S, Castro K, Zhang J, Asp L, Loo H, Laitman BM, Mariani JN, Straus Farber R, Zaslavsky E, Nudelman G, Raine CS, John GR (2015) Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions. Brain 138:1548–1567.  https://doi.org/10.1093/brain/awv077 CrossRefGoogle Scholar
  14. Choi J, Lee H-W, Suk K (2011) Increased plasma levels of lipocalin 2 in mild cognitive impairment. J Neurol Sci 305:28–33.  https://doi.org/10.1016/j.jns.2011.03.023 CrossRefGoogle Scholar
  15. Cohen RA, de la Monte S, Gongvatana A, Ombao H, Gonzalez B, Devlin KN, Navia B, Tashima KT (2011) Plasma cytokine concentrations associated with HIV/hepatitis C coinfection are related to attention, executive and psychomotor functioning. J Neuroimmunol 233:204–210.  https://doi.org/10.1016/j.jneuroim.2010.11.006 CrossRefGoogle Scholar
  16. Correia S, Cohen R, Gongvatana A, Ross S, Olchowski J, Devlin K, Tashima K, Navia B, Delamonte S (2013) Relationship of plasma cytokines and clinical biomarkers to memory performance in HIV. J Neuroimmunol 265:117–123.  https://doi.org/10.1016/j.jneuroim.2013.09.005 CrossRefGoogle Scholar
  17. D’Elia LF, Satz P, Uchiyama CL, White T (1996) Color trails test: professional manual. Odessa, FL: Psychological Assessment Resources.Google Scholar
  18. Egashira Y, Hua Y, Keep RF et al (2016) Lipocalin 2 and blood-brain barrier disruption in White matter after experimental subarachnoid hemorrhage. Acta Neurochir Suppl 121:131–134.  https://doi.org/10.1007/978-3-319-18497-5_23 CrossRefGoogle Scholar
  19. Elneihoum AM, Falke P, Axelsson L, Lundberg E, Lindgärde F, Ohlsson K (1996) Leukocyte activation detected by increased plasma levels of inflammatory mediators in patients with ischemic cerebrovascular diseases. Stroke 27:1734–1738CrossRefGoogle Scholar
  20. Gandhi N, Saiyed Z, Thangavel S, Rodriguez J, Rao KVK, Nair MPN (2009) Differential effects of HIV type 1 clade B and clade C Tat protein on expression of proinflammatory and antiinflammatory cytokines by primary monocytes. AIDS Res Hum Retrovir 25:691–699.  https://doi.org/10.1089/aid.2008.0299 CrossRefGoogle Scholar
  21. Golden CJ (1975) A group version of the Stroop color and word test. J Pers Assess 39:386–388.  https://doi.org/10.1207/s15327752jpa3904_10 CrossRefGoogle Scholar
  22. González-Scarano F, Martín-García J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5:69–81.  https://doi.org/10.1038/nri1527 CrossRefGoogle Scholar
  23. Hattab S, Guihot A, Guiguet M, et al (2014) Comparative impact of antiretroviral drugs on markers of inflammation and immune activation during the first two years of effective therapy for HIV–1 infection: an observational study. BMC Infect Dis.  https://doi.org/10.1186/1471-2334-14-122
  24. Heaton RK, Clifford DB, Franklin DR, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, For the CHARTER Group (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75:2087–2096.  https://doi.org/10.1212/WNL.0b013e318200d727 CrossRefGoogle Scholar
  25. Imp BM, Rubin LH, Tien PC, Plankey MW, Golub ET, French AL, Valcour VG (2017) Monocyte activation is associated with worse cognitive performance in HIV-infected women with virologic suppression. J Infect Dis 215:114–121.  https://doi.org/10.1093/infdis/jiw506 CrossRefGoogle Scholar
  26. Jang E, Lee S, Kim JH, Kim JH, Seo JW, Lee WH, Mori K, Nakao K, Suk K (2013) Secreted protein lipocalin-2 promotes microglial M1 polarization. FASEB J 27:1176–1190.  https://doi.org/10.1096/fj.12-222257 CrossRefGoogle Scholar
  27. Jones LD, Jackson JW, Maggirwar SB (2016) Modeling HIV-1 induced neuroinflammation in mice: role of platelets in mediating blood-brain barrier dysfunction. PLoS One 11:e0151702.  https://doi.org/10.1371/journal.pone.0151702 CrossRefGoogle Scholar
  28. Joska JA, Westgarth-Taylor J, Myer L, Hoare J, Thomas KGF, Combrinck M, Paul RH, Stein DJ, Flisher AJ (2011) Characterization of HIV-associated neurocognitive disorders among individuals starting antiretroviral therapy in South Africa. AIDS Behav 15:1197–1203.  https://doi.org/10.1007/s10461-010-9744-6 CrossRefGoogle Scholar
  29. 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. JAIDS J Acquir Immune Defic Syndr 60:234–243.  https://doi.org/10.1097/QAI.0b013e318256f3bc CrossRefGoogle Scholar
  30. Kim Y, Kim Y-K, Kim NK, Kim SH, Kim OJ, Oh SH (2014) Circulating matrix metalloproteinase-9 level is associated with cerebral White matter hyperintensities in non-stroke individuals. Eur Neurol 72:234–240.  https://doi.org/10.1159/000362876 CrossRefGoogle Scholar
  31. Klove H (1963) Clinical neuropsychology. Med Clin N Am 47:1647–1658CrossRefGoogle Scholar
  32. Krebs SJ, Slike BM, Sithinamsuwan P, Allen IE, Chalermchai T, Tipsuk S, Phanuphak N, Jagodzinski L, Kim JH, Ananworanich J, Marovich MA, Valcour VG (2016) Sex differences in soluble markers vary before and after the initiation of antiretroviral therapy in chronically HIV-infected individuals. AIDS 30:1533–1542.  https://doi.org/10.1097/QAD.0000000000001096 CrossRefGoogle Scholar
  33. Kumar GSS, Venugopal AK, Kashyap MK et al (2012) Gene expression profiling of tuberculous meningitis co-infected with HIV. J Proteomics Bioinform 05:235–244.  https://doi.org/10.4172/jpb.1000243 CrossRefGoogle Scholar
  34. Langford TD, Letendre SL, Larrea GJ, Masliah E (2003) Changing patterns in the neuropathogenesis of HIV during the HAART era. Brain Pathol 13:195–210CrossRefGoogle Scholar
  35. Li S, Wu Y, Keating SM, du H, Sammet CL, Zadikoff C, Mahadevia R, Epstein LG, Ragin AB (2013) Matrix metalloproteinase levels in early HIV infection and relation to in vivo brain status. J Neuro-Oncol 19:452–460.  https://doi.org/10.1007/s13365-013-0197-3 Google Scholar
  36. Liu H, Xu E, Liu J, Xiong H (2016) Oligodendrocyte injury and pathogenesis of HIV-1-associated neurocognitive disorders. Brain Sci 6:23.  https://doi.org/10.3390/brainsci6030023 CrossRefGoogle Scholar
  37. Lorenzl S, Büerger K, Hampel H, Beal MF (2008) Profiles of matrix metalloproteinases and their inhibitors in plasma of patients with dementia. Int Psychogeriatr 20:67–76.  https://doi.org/10.1017/S1041610207005790 CrossRefGoogle Scholar
  38. 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 57:371–379.  https://doi.org/10.1097/QAI.0b013e3182237e54 CrossRefGoogle Scholar
  39. Maubert ME, Wigdahl B, Nonnemacher MR (2017) Opinion: inhibition of blood-brain barrier repair as a mechanism in HIV-1 disease. Front Neurosci 11:228.  https://doi.org/10.3389/fnins.2017.00228 CrossRefGoogle Scholar
  40. McGuire JL, Gill AJ, Douglas SD, Kolson DL (2015) Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. J Neuro-Oncol 21:439–448.  https://doi.org/10.1007/s13365-015-0333-3 Google Scholar
  41. Mendez-Lagares G, Romero-Sanchez MC, Ruiz-Mateos E, Genebat M, Ferrando-Martinez S, Munoz-Fernandez MA, Pacheco YM, Leal M (2013) Long-term suppressive combined antiretroviral treatment does not normalize the serum level of soluble CD14. J Infect Dis 207:1221–1225.  https://doi.org/10.1093/infdis/jit025 CrossRefGoogle Scholar
  42. Meyerhoff DJ (2001) Effects of alcohol and HIV infection on the central nervous system. Alcohol Res Health 25:288–298Google Scholar
  43. Moore DJ, Masliah E, Rippeth JD, Gonzalez R, Carey CL, Cherner M, Ellis RJ, Achim CL, Marcotte TD, Heaton RK, Grant I (2006) Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment. AIDS 20:879–887.  https://doi.org/10.1097/01.aids.0000218552.69834.00 CrossRefGoogle Scholar
  44. Morieri ML, Guardigni V, Sanz JM, Dalla Nora E, Soavi C, Zuliani G, Sighinolfi L, Passaro A (2018) Adipokines levels in HIV infected patients: Lipocalin-2 and fatty acid binding protein-4 as possible markers of HIV and antiretroviral therapy-related adipose tissue inflammation. BMC Infect Dis 18:10.  https://doi.org/10.1186/s12879-017-2925-4 CrossRefGoogle Scholar
  45. Naudé P, den BJ, Comijs H et al (2014) The association of neutrophil gelatinase-associated Lipocalin with cognitive performance in late-life depression and its interactions with gender. Alzheimers Dement 10:P520–P521.  https://doi.org/10.1016/j.jalz.2014.05.812 CrossRefGoogle Scholar
  46. Pajevic S, Basser PJ, Fields RD (2014) Role of myelin plasticity in oscillations and synchrony of neuronal activity NIH public access. Neuroscience 276:135–147.  https://doi.org/10.1016/j.neuroscience.2013.11.007 CrossRefGoogle Scholar
  47. Rao VR, Neogi U, Talboom JS, Padilla L, Rahman M, Fritz-French C, Gonzalez-Ramirez S, Verma A, Wood C, Ruprecht RM, Ranga U, Azim T, Joska J, Eugenin E, Shet A, Bimonte-Nelson H, Tyor WR, Prasad VR (2013) Clade C HIV-1 isolates circulating in southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence. Retrovirology 10:61.  https://doi.org/10.1186/1742-4690-10-61 CrossRefGoogle Scholar
  48. Richert Q, Trajtman A, Arroyave L, Toews J, Becker M, Kasper K, McLaren P, Rueda Z, Keynan Y (2017) Systemic inflammation before and after antiretroviral therapy initiation as a predictor of immune response among HIV-infected individuals in Manitoba. Cytokine 91:74–81.  https://doi.org/10.1016/j.cyto.2016.12.010 CrossRefGoogle Scholar
  49. Shah A, Gangwani MR, Chaudhari NS, Glazyrin A, Bhat HK, Kumar A (2016) Neurotoxicity in the Post-HAART era: caution for the antiretroviral therapeutics. Neurotox Res 30:677–697.  https://doi.org/10.1007/s12640-016-9646-0 CrossRefGoogle Scholar
  50. Sporer B, Paul R, Koedel U, Grimm R, Wick M, Goebel FD, Pfister HW (1998) Presence of matrix metalloproteinase-9 activity in the cerebrospinal fluid of human immunodeficiency virus-infected patients. J Infect Dis 178:854–857CrossRefGoogle Scholar
  51. Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, Wiltshire T, Orth AP, Vega RG, Sapinoso LM, Moqrich A, Patapoutian A, Hampton GM, Schultz PG, Hogenesch JB (2002) Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci U S A 99:4465–4470.  https://doi.org/10.1073/pnas.012025199 CrossRefGoogle Scholar
  52. Uthman OA, Magidson JF, Safren SA, Nachega JB (2014) Depression and adherence to antiretroviral therapy in low-, middle- and high-income countries: a systematic review and meta-analysis. Curr HIV/AIDS Rep 11:291–307.  https://doi.org/10.1007/s11904-014-0220-1 CrossRefGoogle Scholar
  53. Wainberg MA (2004) HIV-1 subtype distribution and the problem of drug resistance. AIDS 18(Suppl 3):S63–S68CrossRefGoogle Scholar
  54. Wesselingh SL, Takahashi K, Glass JD, McArthur JC, Griffin JW, Griffin DE (1997) Cellular localization of tumor necrosis factor mRNA in neurological tissue from HIV-infected patients by combined reverse transcriptase/polymerase chain reaction in situ hybridization and immunohistochemistry. J Neuroimmunol 74:1–8CrossRefGoogle Scholar
  55. Wong JK, Campbell GR, Spector SA (2010) Differential induction of interleukin-10 in monocytes by HIV-1 clade B and clade C Tat proteins. J Biol Chem 285:18319–18325.  https://doi.org/10.1074/jbc.M110.120840 CrossRefGoogle Scholar
  56. Wu JQ, Sassé TR, Saksena MM, Saksena NK (2013) Transcriptome analysis of primary monocytes from HIV-positive patients with differential responses to antiretroviral therapy. Virol J 10:361.  https://doi.org/10.1186/1743-422X-10-361 CrossRefGoogle Scholar
  57. Xing Y, Shepherd N, Lan J, Li W, Rane S, Gupta SK, Zhang S, Dong J, Yu Q (2017) MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders. Brain Behav Immun 65:161–172.  https://doi.org/10.1016/j.bbi.2017.04.024 CrossRefGoogle Scholar
  58. Yuan L, Qiao L, Wei F, Yin J, Liu L, Ji Y, Smith D, Li N, Chen D (2013) Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China. J Neuro-Oncol 19:144–149.  https://doi.org/10.1007/s13365-013-0150-5 Google Scholar
  59. Yuan L, Liu A, Qiao L, et al (2015a) The relationship of CSF and plasma cytokine levels in HIV infected patients with neurocognitive impairment. Biomed Res Int.  https://doi.org/10.1155/2015/506872
  60. Yuan L, Yuan L, Qiao L et al (2015b) Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China.  https://doi.org/10.1007/s13365-013-0150-5

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Authors and Affiliations

  1. 1.Department of Psychiatry and Mental Health and Neuroscience Institute, Brain Behaviour Unit, Groote Schuur HospitalUniversity of Cape TownCape TownSouth Africa
  2. 2.SU/UCT MRC Unit on Risk and Resilience in Mental Disorders and Department of Psychiatry and Mental HealthUniversity of Cape TownCape TownSouth Africa
  3. 3.Division of Neuropsychiatry, Department of Psychiatry and Mental Health, Faculty of Health SciencesUniversity of Cape TownCape TownSouth Africa

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