Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda

J Neurovirol. 2017 Jun;23(3):369-375. doi: 10.1007/s13365-016-0505-9. Epub 2016 Dec 19.


In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/μL (N = 38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium-binding protein B (S100B) and lower levels of amyloid β42. Individuals with CD4 351-500 cells/μL (N = 40) had significantly higher CSF levels of interleukin (IL)-1β, amyloid β42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n = 22) or HIV-associated dementia (n = 15) compared with normal function (n = 30) or asymptomatic neurocognitive impairment (n = 11). Increased levels of interferon (IFN)-γ were associated with increased odds of mild neurocognitive impairment or HIV-associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND.

Keywords: Cytokine expression; Dementia; HIV-associated neurocognitive disorders; Inflammation; Neurodegenerative biomarkers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Dementia Complex / cerebrospinal fluid*
  • AIDS Dementia Complex / diagnosis*
  • AIDS Dementia Complex / immunology
  • AIDS Dementia Complex / physiopathology
  • Adult
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Peptides / immunology
  • Biomarkers / cerebrospinal fluid
  • Brain-Derived Neurotrophic Factor / cerebrospinal fluid
  • Brain-Derived Neurotrophic Factor / immunology
  • CD4 Lymphocyte Count
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / cerebrospinal fluid
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Humans
  • Interleukin-12 / cerebrospinal fluid
  • Interleukin-12 / immunology
  • Interleukin-2 / cerebrospinal fluid
  • Interleukin-2 / immunology
  • Male
  • Matrix Metalloproteinase 1 / cerebrospinal fluid
  • Matrix Metalloproteinase 1 / immunology
  • Matrix Metalloproteinase 7 / cerebrospinal fluid
  • Matrix Metalloproteinase 7 / immunology
  • Middle Aged
  • Neuropsychological Tests
  • Peptide Fragments / cerebrospinal fluid
  • Peptide Fragments / immunology
  • Platelet-Derived Growth Factor / cerebrospinal fluid
  • Platelet-Derived Growth Factor / immunology
  • Prospective Studies
  • Receptor for Advanced Glycation End Products / blood
  • Receptor for Advanced Glycation End Products / immunology
  • S100 Calcium Binding Protein beta Subunit / cerebrospinal fluid
  • S100 Calcium Binding Protein beta Subunit / immunology
  • Tumor Necrosis Factor-alpha / cerebrospinal fluid
  • Tumor Necrosis Factor-alpha / immunology
  • Uganda


  • Amyloid beta-Peptides
  • Biomarkers
  • Brain-Derived Neurotrophic Factor
  • Interleukin-2
  • Peptide Fragments
  • Platelet-Derived Growth Factor
  • Receptor for Advanced Glycation End Products
  • S100 Calcium Binding Protein beta Subunit
  • S100B protein, human
  • Tumor Necrosis Factor-alpha
  • amyloid beta-protein (1-42)
  • platelet-derived growth factor A
  • sRAGE protein, human
  • Interleukin-12
  • BDNF protein, human
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • MMP7 protein, human
  • Matrix Metalloproteinase 7
  • MMP1 protein, human
  • Matrix Metalloproteinase 1