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

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Abstract

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.

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Acknowledgments

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.

Dedication

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.

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Authors and Affiliations

  1. Department of Molecular and Comparative Pathobiology-Retrovirus Laboratory, Baltimore, USA

    Adriana Bora, Ceereena Ubaida Mohien & David R. Graham

  2. Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine Mass Spectrometry and Proteomics Core, Baltimore, USA

    Raghothama Chaerkady

  3. Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, USA

    Linda Chang

  4. Department of Neurology, University of Hawaii, Honolulu, USA

    Adriana Bora, Richard 4th Moxley, Ned Sacktor, Norman Haughey & Justin C. McArthur

  5. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, USA

    Robert Cotter

  6. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    Avindra Nath

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  1. Adriana Bora
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  2. Ceereena Ubaida Mohien
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  11. David R. Graham
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Correspondence to David R. Graham.

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Bora, A., Mohien, C.U., Chaerkady, R. et al. Identification of putative biomarkers for HIV-associated neurocognitive impairment in the CSF of HIV-infected patients under cART therapy determined by mass spectrometry. J. Neurovirol. 20, 457–465 (2014). https://doi.org/10.1007/s13365-014-0263-5

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