HAND Peripheral and CSF Biomarkers: Pitfalls and Promises BJ Brew and T Burdo October 26, 2016
Disclosures • BJ Brew • Relationships with commercial interests • Grants: NIH, NHMRC; Research support: Biogen Idec, Viiv • Patent: QUIN mAB • Speakers Honoraria: Biogen Idec, Viiv, AbbVie • Employee of St Vincent’s Health Australia, University of New South Wales, and University of Notre Dame • Tricia Burdo: • No relationships with commercial interests • No conflicts of interest
Overview • Introduction • Principles and Pitfalls • Individual biomarkers • How each biomarker fits into a practical framework
INTRODUCTION
ART has reduced the severity of HIV-associated neurocognitive disorders Pre ART Post ART (after 1996) Adapted from: McArthur, J. C. et al. (2016) Nat. Rev. Neurol. The Therapeutic Paradox
Neuropsychological impairment rates in those with plasma VL<50 cpml 45 39 38 36 37.5 40 35 30 25 20 21 15 15 --- --- 59 40 10 21 319 276 15 --- ----- ----- --- 5 59 807 717 40 0 Cysique (C-S) Robertson ( C-S) Robertson ( L) Sevigny (L)
HIV comorbidities are associated with chronic low-grade inflammation Cardiovascular disease HAND Bone diseases Chronic Inflammation/ immune activation Metabolic Cancers diseases, diabetes Frality Adapted from: Freund. et al. (2010) Trends Molecular Med
Monocyte and macrophages are important targets of HIV Campbell, J. H. et al. (2014) AIDS
Changes of monocytes during HIV infection Campbell, J. H. et al. (2014) AIDS
Overview of HAND pathogenesis pre cART Neurotropism: CCR5 > CXCR4 Migration of microbial translocation products -Autophagy* 1 2 ubiquitin proteosome system Immunoproteosome** 3 *Gougeon ML et al. Apoptosis 5 2009;14:501-508 **Nguyen TP, et al. Am J Pathol 2010;176:893-902 4 Adapted from Gonzalez-Scarano F et al. Nat Rev Immunol 2005;5:69-81
HAND Cellular Pathogenesis Macrophages: • Critical to HIV mediated neuropathogenesis • Serve as viral reservoirs within the CNS • Release inflammatory mediators and neurotoxic viral and host proteins • Central to HIV-associated neuroinflammation and neurocognitive dysfunction Astrocytes are also crucial but monocytes/macrophages are important from a systemic perspective
Possible causes of sustained CNS inflammation during ART • Latent and low level infection in the brain (CSF viral escape) • Microglia priming (circulating products translocated from gut) • Macrophages- harbors HIV, produce virions and are long-lived • Disturbed cellular energy (infected macrophages release ATP) • Neuronal and synaptic protein dynamics are altered • Contributions from cerebrovascular dysfunction, metabolic alterations, ART regimens
PRINCIPLES AND PITFALLS
Principles • 1. HAND has a unitary pathogenesis: – HAND with viral suppression = HAND without viral suppression? – HAND with HIV encephalitis = HAND without HIV encephalitis (just less inflammation)? – ANI/MND have the same pathogenetic pathway?
Principles • HAND has a unitary pathogenesis: – HAND with viral suppression = driven by viral components eg tat nef etc? – HAND without viral suppression = driven by whole virus especially env?
HAND + HIVE = HAND – HIVE? Neuropsychological impairment Mild/mod Mild/mod Severe Severe Mild/mod Severe 5/9 6/8 5/9 6/8 6/6 5/9 6/8 6/6 6/6 12 10 10 12 12 12 10 10 10 10 --- --- --- --- --- --- --- --- --- --- 59 32 32 32 32 32 32 32 32 32 Modified from Desplats et al Neurol 2013
HAND + HIVE = HAND – HIVE? Gelman et al PLoS One 2012
ANI/MND have the same pathogenetic pathway? • 3 cases of ANI = HIVE ( Cherner et al J Nvirol 2007 ) • 10 cases of mild/moderate neuropsychological impairment = latent HIV only (Desplats et al Neurol 2013)
HAND NEUROVIROLOGY BRAIN Latent infection Productive infection ANI/MND HAD
Principles • 2. HAND is driven by systemic and CNS (CSF/brain) disease (HIV/inflammation) • But: – Systemic and CNS equally? – To differing extents at different time points in HIV disease course?
Mild HAND is prevalent It is driven by It is driven by compartmentalized brain viral Mild HAND is latency burden/activity latency burden/activity Relatively uncommon Relatively uncommon It is driven by peripheral viral latency burden/activity latency burden/activity HIV-associated dementia BBB disrupted Peripheral & CNS viral latency Cysique and Brew unpublished
Principles • 3. Activity of HAND: – Progressing – Regressing – Stable but subclinically active: “simmering pot” – Stable inactive: “legacy” ?evidence • 4. Reparative and remodelling aspects: emerging evidence
EFFECT OF RECENT ARV CHANGE ON BIOMARKER INTERPRETATION Differing Biomarker effects Modified from Cysique et al Neurology 2009
Cysique et al under review
Principles • 5. Account for confounds: – Substance misuse – Hepatitis C – Overlap with other conditions associated with aging: • Vascular disease • Degenerative: Alzheimer’s, Parkinson’s
Pathogenesis of Neurodegenerative Diseases Pathogenic insult misfolded protein stress/toxic proteins inflammation A G Defence failure: Defence failure: H Hsps, ER chaperones, Ubiquitin-proteasome, autophagy, Pic, ?PgP proteasome, autophagy, Pic, ?PgP proteasome, autophagy, Pic, ?PgP E I inflammation A V excitotoxicity mitochondrial dysfunction mitochondrial dysfunction R Oxidative/Nitrosative transcription dysregulation stress V cell dysfunction/death Modified from Brew et al J Neuroimm Pharm 2009
CSF Biomarkers and Age Effect De Oliveira et al Sci Rep 2015
- ↓NAA Age ↑ mIo CVD ↓NAA Inflammation ↑ mIo Inflammation - HIV HIV duration ↓NAA cART Inflammatio n ~ ↑ neopterin ~ ↑ Cr A new model of chronic HAND pathogenesis? Cysique et al PLoS One 2014
Principles • 6. Universality-Selectivity: • all patients are vulnerable? • It is now clear that only some patients are susceptible – – The principle of selectivity
Principles • Biomarkers must developed within latter framework accounting for concepts of activity and repair
Principles: Approach S1oob neopterin Metabolic Trophic Vascular Marcotte et al JNIP 2013 Price et al Neurology 2007
Suggested Solutions • “Clean” large data sets ( not a “wash out” strategy) • Well characterised: – Presence and duration of viral suppression – ARV history – CD4 history – HAND history – Neuropathology
PERIPHERAL BIOMARKERS
Peripheral biomarkers in HIV-associated neurocognitive disorders Tricia Burdo, Ph.D. Associate Professor Neuroscience 215-707-1618 (office) burdot@temple.edu (email)
Biomarkers of HIV-associated dementia (HAD) before ART Decrease CD4+ T cells: current if naïve - permissive effect when <200 cells/μl, even <350 cells/μl (Bhaskaran K et al Ann Neurol 2008) Nadir if experienced (Cysique LA et al. Neurology 2006, Valcour V et al. J Neurovirol 2006, Robertson et al 2007) Anaemia Low Platelets Impaired glucose tolerance esp diabetes (Valcour V et al JAIDS 2005) Plasma viral load CSF viral load CCL2 IL-6 sCD14 Neopterin But none is specific for HAND Kynurenine Quinolinic acid
Peripheral biomarkers of HAND Elevated CD16 + monocytes [Pulliam Lancet 1997,Williams Clin Invest 2005, Campbell Plos One 2011] Elevated sCD14 (receptor for LPS) [Lyons 2011, Ancuta 2008, Royal 2016 ] Monocyte Elevated sCD163 (Burdo 2013, Royal 2016 )- increased in MND related Neither correlate with npsych/HAND but none on cART (McGuire JNvirol 2015 ) Loss of CCR2+ CD14loCD16hi monos (Ndhlovu 2015) CCR2+ on CD14+CD16+ (increased in HAND, not differentiate between ANI, MDN, HAD) CCR2+ on CD14+CD16+ (increased in HAND, not differentiate between ANI, MDN, HAD) (Williams 2014 Neurology) High HIV DNA levels in CD16 + monocytes [Kusao 2012, Valcour et al 2013, Cysique et al 2015] Vascular disease: HT, CVD, hypercholesterolaemia (Wright et al 2010)
Micro RNAs • HAND associations: miR-3665 > miR-4516 > miR-4707–5p • But: small n, no ANI, not virally suppressed Asahchop et al AIDS 2016
Plasma NFL elevated in HAD Gisslen, 2016 But NFL is quickly hydrolysed – cannot use stored samples
Insights from the SIV-infected rhesus macaque model Monocyte expansion in the first CD16+ monocytes peak during weeks of infection predicts the rate acute infection and with AIDS of disease progression Williams K., J Clin Invest 2005 Burdo T., PLoS Pathogens 2010
Monocyte expansion from bone marrow correlates with rapid AIDS, severity of SIVE and sCD163 levels sCD163 plasma is the best correlate of BrdU monocytes Burdo et al. PLos Pathogens, 2010
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