Approach to Cerebrospinal Fluid (CSF) Biomarker Discovery and Evaluation in HIV Infection

Abstract

Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previously-defined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.

A comparison of two post-processing analysis methods to quantify cerebral metabolites measuredviaproton magnetic resonance spectroscopy in HIV disease

“…6 Furthermore, potential plasma biomarkers have shown little specificity in detecting HIV-associated cognitive disorders. 7 Although cerebrospinal fluid (CSF) markers are considered a more valuable clinical tool, 8 the requirement for CSF examination is challenging, and less invasive methods are preferable. Measurement of cerebral metabolites as biomarkers, via proton-MR spectroscopy ( 1 H-MRS), is one attractive approach for the assessment of cerebral function in HIV disease.…”

Chronic Infectious Inflammatory Diseases of the Central Nervous System

“…The neopterin levels in patients receiving effective antiretroviral treatment are low but still greater than in HIV negative controls (Price et al 2013 ).…”

“…The immunological markers that have been studied include neopterin as a cardinal marker but also other soluble markers such as chemokines CCL2 (MCP-1, monocyte chemokine protein 1), CXCL10 (IP-10, interferon protein 10) and β2M (beta-2-microglobulin); a component of the MHC-I complex increased in CSF in HIV-associated dementia; and TNFα (tumour necrosis factor alpha), sCD14 (a soluble LPS ligand), sCD163 (a macrophage chemokine), sVCAM-1 (soluble vascular adhesion molecule 1), MMP-9 (matrix metallopeptidase 9) and TIMP-1 (tissue inhibitor of metalloproteinases 1). All these markers mostly indicate the presence of CNS infl ammation during HIV infection rather being specifi c for HIV infection (Price et al 2013 ).…”

Neues bei HIV und Neuro-Aids

“…Therapieverlaufs nimmt die Analyse spezifischer Biomarker ein [93,96]. Ein wertvoller Marker ist die Bestimmung der HIV-1-RNA im Liquor.…”

“…Diese kann bereits bei klinisch-neurologisch unauffälligen Patienten nachgewiesen werden und kann bei intakter Blut-Hirn-Schranke auf eine lokale, intrazerebrale Replikation des Virus hinweisen. Im Rahmen dieser Kompartmentbildung haben etwa 16 -20 % aller asymptomatischen HIV-Patienten eine stärkere Virusreplikation im Liquor als im Blut [93]. Bei unbehandelten, asymptomatischen Patienten bleibt die HIV-1-RNA im Liquor über Jahre relativ konstant (> 50 Kopien/ml), steigt aber bei Patienten mit einer HIV-Enzephalopathie signifikant an, wobei die höchsten Werte bei der HIV-assoziierten Demenz und der akuten HIV-Meningoenzephalitis erreicht werden [94,95].…”