Soluble CD14 in cerebrospinal fluid is associated with markers of inflammation and axonal damage in untreated HIV-infected patients: a retrospective cross-sectional study.
BACKGROUND
HIV-associated cognitive impairment has declined since the introduction of combination antiretroviral treatment (cART). However, milder forms of cognitive impairment persist. Inflammation in the cerebrospinal fluid (CSF) has been associated with cognitive impairment, and CSF neurofilament light chain protein (NFL) and CSF neopterin concentrations are increased in those patients. Microbial translocation in HIV infection has been suggested to contribute to chronic inflammation, and lipopolysaccharide (LPS) and soluble CD14 (sCD14) are markers of microbial translocation and the resulting monocyte activation, respectively. We hypothesised that microbial translocation contributes to inflammation and axonal damage in the central nervous system (CNS) in untreated HIV infection.


METHODS
We analyzed paired samples of plasma and CSF from 62 HIV-infected, untreated patients without cognitive symptoms from Sahlgrenska University Hospital, Gothenburg, Sweden. Measurements of neopterin and NFL in CSF were available from previous studies. Plasma and CSF sCD14 was measured using ELISA (R&D, Minneapolis, MN), and plasma and CSF LPS was measured using LAL colorimetric assay (Lonza, Walkersville, MD, USA). Univariate and multivariate regression analyses were performed.


RESULTS
LPS in plasma was associated with plasma sCD14 (r = 0.31, P = 0.015), and plasma sCD14 was associated with CSF sCD14 (r = 0.32, P = 0.012). Furthermore, CSF sCD14 was associated with NFL (r = 0.32, P = 0.031) and neopterin (r = 0.32, P = 0.012) in CSF. LPS was not detectable in CSF. In a multivariate regression model CSF sCD14 remained associated with NFL and neopterin after adjusting for age, CD4+ cell count, and HIV RNA in CSF.


CONCLUSIONS
In a group of untreated, HIV-infected patients LPS was associated with sCD14 in plasma, and plasma sCD14 was associated CSF sCD14. CSF sCD14 were associated with markers of CNS inflammation and axonal damage. This suggest that microbial translocation might be a driver of systemic and CNS inflammation. However, LPS was not detectable in the CSF, and since sCD14 is a marker of monocyte activation sCD14 may be increased due to other causes than microbial translocation. Further studies regarding cognitive impairment and biomarkers are warranted to fully understand causality.
Department of Infectious Diseases, Viro-immunology Research Unit, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK 2100, Copenhagen Ø, Denmark.
Sofie
S
Jespersen
Department of Infectious Diseases, Viro-immunology Research Unit, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK 2100, Copenhagen Ø, Denmark.
Karin Kæreby
KK
Pedersen
Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Birgitta
B
Anesten
Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
Henrik
H
Zetterberg
Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
Dietmar
D
Fuchs
Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Magnus
M
Gisslén
Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Lars
L
Hagberg
Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.
Marius
M
Trøseid
Department of Infectious Diseases, Viro-immunology Research Unit, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK 2100, Copenhagen Ø, Denmark. sdn@dadlnet.dk.
Susanne Dam
SD
Nielsen
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D018791:CD4 Lymphocyte Count; D002490:Central Nervous System / Q000378:metabolism; D003124:Colorimetry; D003430:Cross-Sectional Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015658:HIV Infections / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D018950:Lipopolysaccharide Receptors / Q000097:blood / Q000134:cerebrospinal fluid*; D008070:Lipopolysaccharides / Q000032:analysis / Q000097:blood; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D019798:Neopterin / Q000134:cerebrospinal fluid; D016900:Neurofilament Proteins / Q000134:cerebrospinal fluid; D012044:Regression Analysis; D012189:Retrospective Studies; D013548:Sweden
D015415:Biomarkers; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016900:Neurofilament Proteins; C044882:neurofilament protein L; D019798:Neopterin
CNS inflammation; HIV; Microbial translocation; NFL; Neopterin; sCD14