Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection

• Published in: PloS one Vol. 9; no. 12; p. e116081
• Main Authors: Peterson, Julia, Gisslen, Magnus, Zetterberg, Henrik, Fuchs, Dietmar, Shacklett, Barbara L, Hagberg, Lars, Yiannoutsos, Constantin T, Spudich, Serena S, Price, Richard W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.12.2014; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; Alzheimer Disease; Alzheimer Disease - cerebrospinal fluid; Alzheimer's disease; Amyloid beta-Peptides; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid beta-Protein Precursor; Amyloid beta-Protein Precursor - cerebrospinal fluid; Antiretroviral drugs; Biological markers; Biology and Life Sciences; Biomarkers; Biomarkers - cerebrospinal fluid; CD4 antigen; Central nervous system; Cerebrospinal fluid; Chronic infection; Clinical Medicine; Comparative analysis; complications; Cross-Sectional Studies; diagnosis; Disseminated infection; Evolution; Female; Health aspects; HIV; HIV (Viruses); HIV - isolation & purification; HIV infection; HIV Infections; HIV Infections - cerebrospinal fluid; HIV Infections - complications; HIV Infections - diagnosis; Human immunodeficiency virus; Humans; Injuries; isolation & purification; Klinisk medicin; Lymphocytes; Lymphocytes T; Male; Medicine and Health Sciences; Metabolites; Middle Aged; Nervous System Diseases; Nervous System Diseases - cerebrospinal fluid; Nervous System Diseases - complications; Neurodegenerative diseases; Neurofilament Proteins; Neurofilament Proteins - cerebrospinal fluid; Neurons; Norms; Peptide Fragments; Peptide Fragments - cerebrospinal fluid; Peptides; Phosphorylation; Proteins; T cells; Tau protein; tau Proteins; tau Proteins - cerebrospinal fluid; San Francisco California; Sweden; California; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0116081

The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and <50 cells/µL; HAD; treatment-induced viral suppression; and 'elite' controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ) and amyloid beta (Aβ) fragments 1-42, 1-40 and 1-38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50-199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis, diagnosis and management.