Monocyte Activation Markers in Cerebrospinal Fluid Associated With Impaired Neurocognitive Testing in Advanced HIV Infection

Abstract

Background Activated monocytes/macrophages play a role in severe forms of HIV-associated neurocognitive disorders (HAND), but little is known about mechanisms driving milder forms that are prevalent despite combination antiretroviral therapy (cART). To examine relationships of monocyte activation markers to HAND of varying severity, we compared plasma and CSF biomarker levels to neurocognitive test scores in HIV+ subjects. Methods Plasma and CSF sCD14, CCL2, and IL-6 were measured by ELISA in 67 HIV+ subjects with nadir CD4 <300, and CSF inflammatory biomarkers were measured by multiplex assay in 14 subjects on suppressive cART. Results 82% were on cART, with 31% having undetectable plasma VL. CSF sCD14 was increased in subjects with impaired neurocognitive testing (p=0.02), correlated inversely with global T scores in subjects with detectable but not undetectable plasma VL (p=0.02), and yielded higher AUROC values for predicting impaired T scores (0.659) than plasma or CSF VL and current or nadir CD4 counts in single-marker and multivariate models. CSF sCD14, IL-6, IL-8, CCL2, CCL3, CXCL10, and IFNγ were increased in subjects on suppressive cART regardless of cognitive status and predicted patient class in unsupervised analyses, with IL-8, CCL2, and IFNγ explaining most of the variance. Conclusions CSF sCD14 is associated with impaired neurocognitive testing in HIV patients on nonsuppressive cART, suggesting potential utility as a biomarker to monitor HAND progression. CSF sCD14, IL-6, IL-8, CCL2, CCL3, CXCL10, and IFNγ remain elevated in patients on suppressive cART regardless of cognitive status, implying ongoing intrathecal inflammation even in the absence of clinical manifestations.

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

“…The CSF CXCL10 levels in our patients were similar to or in some cases higher than those reported previously in the literature for MS patients and were also higher than values seen in normal CSF 15. Although CSF CXCL10 elevation has been reported in other disease states,16, 17, 18 this is the first report to our knowledge that PND patients have elevated CSF CXCL10. CCL2 was also detected in PND patient CSF pretreatment, but levels were comparable to those reported for normal individuals (data not shown).…”

Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders

“…We have identified IFN-γ as a candidate cellular factor that decreases astrocyte HO-1 expression, which could thus be responsible for the HO-1 deficiency observed in the prefrontal cortex and striatum of HIVinfected individuals. IFN-γ has been shown to be elevated in the CNS of HIV-infected individuals (48,49), even aviremic subjects on suppressive ART (52). We have shown that IFN-γ can reduce the expression of HO-1 in both human astrocytes and noninfected human macrophages, a finding previously described in IFN-γ-treated human glioblastoma cells and human retinal pigment endothelial cells (58,59).…”

“…These results suggest that the HO-1 deficiency in HIV-infected brain could result from macrophage HO-1 loss induced by HIV replication and astrocyte HO-1 loss induced by IFN-γ signaling. Consistent with this hypothesis, elevated CSF levels of IFN-γ are found in HIV + patients, even those on suppressive ART (52).…”

Soluble biomarkers of HIV transmission, disease progression and comorbidities

“…Elevated plasma concentrations of sCD14 are furthermore associated with increased rates of carotid artery intima-media thickening, a surrogate marker for progression of subclinical atherosclerosis [48]. Interestingly, levels of sCD14 in plasma and CSF are also linked with neurocognitive impairment in advanced HIV-1 infection despite suppressive ART [49,50]. Levels of the soluble scavenger receptor for haemoglobin, CD163, are elevated in both early and chronic infection, and parallel to viral load and associated with monocyte expansion [51].…”