Journal of NeuroVirology

, Volume 20, Issue 5, pp 457–465 | Cite as

Identification of putative biomarkers for HIV-associated neurocognitive impairment in the CSF of HIV-infected patients under cART therapy determined by mass spectrometry

  • Adriana Bora
  • Ceereena Ubaida Mohien
  • Raghothama Chaerkady
  • Linda Chang
  • Richard 4th Moxley
  • Ned Sacktor
  • Norman Haughey
  • Justin C. McArthur
  • Robert Cotter
  • Avindra Nath
  • David R. GrahamEmail author


We identified and measured proteins in the cerebral spinal fluid (CSF) involved in HIV-associated neurological disorders. Protein levels were determined by mass spectrometry (MS) in pooled CSF taken from three patient groups (human immunodeficiency virus (HIV)-1-infected patients that developed HIV-associated neurocognitive disorders (HANDs), HIV-1-infected patients without HAND, and healthy controls). Pools were generated from 10 patients each per group. CSF from individual patient groups were digested with trypsin and separately labeled using with isobaric tags for relative and absolute quantitation (iTRAQ). After combining all samples in one, peptides were extensively fractionated by offline two-dimensional separation and identified by tandem MS. One hundred and ninety three proteins were deemed to be interpretable for quantitation based on permutation tests with a 95 % confidence interval with a p value ≤ 0.05. Using a cutoff of 1.5-fold for upregulation and 0.6 for downregulation, 16 proteins were differentially expressed in HIV + HAND (reporter p value ≤0.05) with seven of them previously described as HIV-interacting proteins: endoplasmin, mitochondrial damage mediator-BH3-interacting domanin death agonist, orosomucoid, apolipoprotein E, metalloproteinase inhibitor 2, peroxiredoxin-2, and the nuclear protein, ruvB-like 2. Several previously unidentified proteins with possible neurological implication in HIV patients include forming-binding protein 1, C-reactive protein, leukocyte-associated immunoglobulin receptor 1, renin receptor, mediator of RNA polymerase II transcription subunit 14, multimerin-2, alpha-N-acetylglucosaminidase, caldesmon, and cadherin EGF LAG G-type receptor. Our results suggest that not only a few but possibly a combination of biomarkers that are highly correlated can predict neurocognitive status in HIV-infected patients and might be involved in monocyte or macrophage activation.


Mass spectrometry i-TRAQ HIV Biomarker Proteomics 



The authors would like to acknowledge the following funding sources for this work: Center for Novel Therapeutics for HIV-Associated Cognitive Disorders, NIMH Center grant 2P30MH075673, and NHLBI Contract No. HHSN268201000032C. CSF was collected from patients that provided informed consent and under protocols approved by the appropriate institutional review boards. We would like to acknowledge that mass spectrometry for these studies were performed in the Johns Hopkins University School of Medicine Mass Spectrometry and Proteomics Core facility (Dr. Robert Cole, Director).

Conflict of interest

The authors declare they have no financial relationship with the organization that sponsors this research; therefore, they have no conflict of interest.


The authors would like to dedicate this manuscript to the late Dr. Robert Cotter, who passed away during the preparation of this manuscript. His friendship, guidance, and support will be greatly missed.

Supplementary material

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Copyright information

© Journal of NeuroVirology, Inc. 2014

Authors and Affiliations

  • Adriana Bora
    • 1
    • 4
  • Ceereena Ubaida Mohien
    • 1
  • Raghothama Chaerkady
    • 2
  • Linda Chang
    • 3
  • Richard 4th Moxley
    • 4
  • Ned Sacktor
    • 4
  • Norman Haughey
    • 4
  • Justin C. McArthur
    • 4
  • Robert Cotter
    • 5
  • Avindra Nath
    • 6
  • David R. Graham
    • 1
    Email author
  1. 1.Department of Molecular and Comparative Pathobiology-Retrovirus LaboratoryBaltimoreUSA
  2. 2.Johns Hopkins School of MedicineJohns Hopkins University School of Medicine Mass Spectrometry and Proteomics CoreBaltimoreUSA
  3. 3.Department of Medicine, John A. Burns School of MedicineUniversity of HawaiiHonoluluUSA
  4. 4.Department of NeurologyUniversity of HawaiiHonoluluUSA
  5. 5.Department of Pharmacology and Molecular SciencesJohns Hopkins School of MedicineBaltimoreUSA
  6. 6.National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaUSA

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