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.