Biomarkers in HIVRelated CNS Disease: I CSF

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Biomarkers in HIV-Related CNS Disease I CSF
Blood
Toward developing pathobiologically-based,
objective methods for disease definition,
diagnosis and management in advanced and
resource-poor settings
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Biomarkers I CSF Blood

• Need
• Objective markers of disease
• Diagnosis
• Assessing disease activity
• Assessing treatment targets
• Evaluating treatment responses
• Predicting disease development
• Potential Tools
• CSF markers
• Blood markers
• Spectra of Settings
• Medically prosperous to resource-poor
• Research (clinical trials, pathogenetic studies,
  etc.) to clinical practice

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Biomarkers I Pathogenetic Basis
Immune Dysregulation
HIV
HIV Encephalitis
Brain Injury
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Biomarker Targets3 Cardinal Elements

• HIV
• Immune System
• Brain

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HIV Markers

• Methods (present potential)
• Quantitative measures of virus or products
• HIV RNA
• Toxic gene products (gp120, tat)
• Viral characteristics
• Tropism
• Neurotropism
• Genetic compartmentalization
• Fitness/Resistance
• Neuropathogenicity
• Issues
• Fundamental problem Background of ubiquitous
  HIV infection
• Conversely, question Is CSF infection always
  detected in active CNS disease?

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Immunological Markers

• Methods (examples)
• Soluble markers
• MF/microglial activation
• Neopterin
• MCP-1 (CXCL2)
• Quinolinic acid
• More general cell activation
• ß2M
• IP-10 (CXCL10)
• Cell markers
• Monocyte activation
• CD16, CD69
• Issues
• Fundamental problem Background of immune
  activation
• Conversely, question Is immune activation always
  present in active CNS disease?

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Brain Markers

• Methods (examples)
• Neuronal injury markers
• Neural filament protein
• Tau
• Glial (macro) activation/turnover markers
• GFAP
• S-100 protein
• Barrier injury
• Albumin ratio
• Issues
• Sensitivity Is detection of these markers in CSF
  or blood sufficiently sensitive?
• Specificity Abnormalities can be present in
  other CNS conditions

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Nonspecificity of CSF Examples
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Combined Approach to Diagnosis and Disease
Activity

• 3-Element combination marker profile using
  existing markers (examples)
• HIV
• CSF HIV RNA
• Immune activation
• MF activation
• CSF Neopterin or MCP-1
• Blood monocyte CD69 or CD16
• Neural injury marker
• NFL
• Similar paradigm signal pattern on proteomics or
  other tools that sample multiple marker types

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Development of Useful Biomarkers

• Properties
• Sensitive
• Specific
• Alone or in combination
• Easily measured
• Reliable
• Wide dynamic range or low concentrations in
  normals
• Inexpensive and transportable
• Blood test over CSF if possible
• Follow leads of pathogenesis
• But focus on marker use, not mediator role
• Neopterin gt or MCP-1 gt TNFa

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Challenges of Biomarker Disease Definition

• Range of clinical presentations
• Encephalopathy/dementia
• Myelopathy
• Organic psychosis
• Spectrum of disease activity
• Progressing/active
• Improving (responding to treatments)
• Inactive
• In presence of confounders
• Static/longterm encephalopathies
• Concurrent encephalopathies/meningidites
• Continued search for novel, superior markers
• Application in resource-poor settings
• To define diseases rather than syndromes

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Subcommittee on Biomarkers I

• Paola Cinque, San Raffaele Hospital, Milan, Italy
• Magnus Gisslén, Göteborg University, Göteborg,
  Sweden
• Richard W Price, UCSF, San Francisco, USA
• Lynn Pulliam, San Francisco, UCSF, USA

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Application