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

Kamat, Anupa PhD*; Lyons, Jennifer L. MD*; Misra, Vikas MS*; Uno, Hajime PhD*; Morgello, Susan MD; Singer, Elyse J. MD; Gabuzda, Dana MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1st, 2012 - Volume 60 - Issue 3 - p 234–243
doi: 10.1097/QAI.0b013e318256f3bc
Basic and Translational Science

Background: Activated monocytes/macrophages play a role in severe forms of HIV-associated neurocognitive disorders (HAND), but little is known about the 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 cerebrospinal fluid (CSF) biomarker levels with neurocognitive test scores in HIV+ subjects.

Methods: Plasma and CSF soluble CD14 (sCD14), CCL2, and interleukin (IL) 6 were measured by enzyme-linked immunosorbent assay in 67 HIV+ subjects with nadir CD4 <300, and CSF inflammatory biomarkers were measured by multiplex assay in 14 subjects on suppressive cART.

Results: Eighty-two percent were on cART, with 31% having undetectable plasma viral load (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 area under the receiver operating characteristic curve 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 interferon (IFN) gamma 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 patients with HIV 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.

*Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Mount Sinai Medical Center, New York, NY

University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA.

Correspondence to: Dana Gabuzda, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue, CLS 1010, Boston, MA 02115(e-mail: dana_gabuzda@dfci.harvard.edu).

Supported by National Institutes of Health Grant DA26322, DA28994, and MH083588 to D. Gabuzda and a Mount Sinai Institute for NeuroAIDS Disparities Scholar Grant (funded through R25MH080663) to J. L. Lyons National NeuroAIDS Tissue Consortium sites were supported by National Institutes of Health Grants U01MH083501, R24MH59724, U01MH083506, R24MH59745, U01MH083507, R24 NS45491, 5U01MH083500, NS38841, U01MH083545, and N01MH32002. CNS HIV Antiretroviral Therapy Effects Research was supported by N01MH22005. Core facilities were supported by the Harvard Center for AIDS Research and Dana-Farber Cancer Institute/Harvard Center for Cancer Research grants.

The authors have no conflicts of interest to disclose.

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Received November 16, 2011

Accepted March 22, 2012

© 2012 Lippincott Williams & Wilkins, Inc.