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Alterations in the Levels of Vesicular Trafficking Proteins Involved in HIV Replication in the Brains and CSF of Patients with HIV-associated Neurocognitive Disorders

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Abstract

Human immunodeficiency virus (HIV) associated neurocognitive disorders (HAND) remain prevalent despite improved antiretroviral therapies. A HAND-specific biomarker indicative of neuropsychological impairment (NPI) would give insight into disease progression and aid clinicians in designing therapy. Endosomal sorting complex required for transport (ESCRT) proteins such as tumor susceptibility gene (TSG)-101, vacuolar protein sorting (VPS)-4 and LIP-5 are important for HIV replication and recently antiviral interferon stimulated gene (ISG)-15 was proposed as a biomarker for CNS injury. Here, we analyzed a well-characterized cohort of HIV+ cerebral spinal fluid (CSF) and postmortem brain specimens for multiple vesicular trafficking proteins and a related innate immune protein, ISG-15, TSG-101, VPS-4 and LIP-5. All protein levels trended higher with increased NPI and neuropathology. ISG-15 CSF levels were increased in HIV encephalitis (HIVE) compared to normal cases, and three quarters of HIVE samples had above average CSF ISG-15 levels. VPS-4 CSF levels were increased in NPI/NPI-O compared to normal patients. VPS-4 CSF levels in HIV-associated dementia were equivalent to that of normal patients. LIP-5 CSF levels positively correlate with ISG-15 levels, and higher than average ISG-15 levels indicate elevated viral load. Immunoblot and immunohistochemical analyses show increased expression of ISG-15, VPS-4 and LIP-5 in neuronal cell bodies and astroglial cells. ESCRT protein CSF levels analyzed in conjunction with viral load may be indicative of NPI stage, and may aid in the diagnosis and design of therapies for HIV patients. Further studies on the ESCRT protein expression during HIV infection may lead to a promising biomarker for predicting progression of NPI.

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Acknowledgments

We thank the National Institutes of Aging (AG043384), the National Institutes of Mental Health (MH062962, MH5974 and MH83506) and the National Institute for Neurological Disorders and Stroke (1F32NS083426-01) funding this work.

Conflict of interest

The authors of this manuscript declare that there are no actual or potential conflicts of interest. The authors affirm that there are no financial, personal or other relationships with other people or organizations that have inappropriately influenced or biased their research.

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Authors and Affiliations

  1. Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA

    Jerel Fields, Wilmar Dumaop & Eliezer Masliah

  2. Department of Neurosciences, University of California San Diego, 9500 Gilman Dr., MTF 348, La Jolla, CA, 92093, USA

    Anthony Adame, Ronald J. Ellis & Eliezer Masliah

  3. Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA

    Scott Letendre

  4. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA

    Igor Grant

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  1. Jerel Fields
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  2. Wilmar Dumaop
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  7. Eliezer Masliah
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Correspondence to Eliezer Masliah.

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Jerel Fields and Wilmar Dumaop contributed equally to manuscript.

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Fields, J., Dumaop, W., Adame, A. et al. Alterations in the Levels of Vesicular Trafficking Proteins Involved in HIV Replication in the Brains and CSF of Patients with HIV-associated Neurocognitive Disorders. J Neuroimmune Pharmacol 8, 1197–1209 (2013). https://doi.org/10.1007/s11481-013-9511-3

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