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YWHAE/14-3-3ε: a potential novel genetic risk factor and CSF biomarker for HIV neurocognitive impairment

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Abstract

YWHAE (14-3-3ε) protein levels are considered to be a reliable biomarker for neurodegeneration. The YWHAE protein interacts both directly and indirectly with human immunodeficiency virus (HIV) accessory proteins, leading to cell death. The purpose of this study was to examine the relationship between YWHAE polymorphisms and HIV-associated neurocognitive disorder (HAND) and the relationship between YWHAE protein levels and HAND. A cross-sectional study using random samples of HIV-seropositive (n = 20) and HIV-seronegative (controls) (n = 16) women from the Hispanic-Latino Longitudinal Cohort of Women was conducted. Individuals who are HIV-seropositive and heterozygous at the rs4790084/rs1204828 loci in the YWHAE gene were 3× more likely to display reduced cognitive functioning, to have received a HAND diagnosis, and to have less YHWAE protein expressed than homozygotes. Western blots from cerebral spinal fluid indicate that the HIV-seropositive women with HAND expressed 4.5× less YWHAE compared to HIV-seropositive cognitively normal women (94 % sensitivity, 84 % specificity; HIV-seropositive vs. controls). Therefore, polymorphism in YWHAE may be a genetic risk factor for HAND and levels of YWHAE protein are a likely biomarker for neurocognitive status in HIV-seropositive women.

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Acknowledgments

The study was funded by National Center for Research Resources (NCRR) grant 1U54RR026139-01A1 and the National Institute on Minority Health and Health Disparities 8U54MD007587 to the University of Puerto Rico Medical Science Campus, and National Institute of Mental Health (NIMH) Center for Novel Therapeutics of HIV-associated Cognitive Disorders Pilot Project Grant G12 RR003050 to the John Hopkins University. The study was supported partially by National Institute of Neurological Disorders and Stroke (NINDS) grants S11NS46278 and U54NS43011 (SNRP). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of NCRR, NIMHD, NIMH, or NINDS. Thanks to Dr. Carlos Pardo at John Hopkins University for the control CSF samples. Thanks to Dr. Jacob Raber at Oregon Health & Science University for permission to use the Memory Island and for serving as an excellent mentor. Also we appreciate the contribution from Dr. Raul Mayo who conducted neuropsychological testing of cohort participants and Dr. Avindra Nath for his contribution in the development of the cohort and for his continuous collaboration with the SNRP. We acknowledge the support of Tirtsa Porrata-Doria and the Molecular Biology Core Lab (Grant RR003050). Special thanks go to Robert Ritchie of the RCMI Publications Office (G12 RR003050). I would like to thank Madeline Collazo for her help with genotyping.

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Authors and Affiliations

  1. Department of Physiology, Pharmacology, and Toxicology, Ponce School of Medicine and Health Sciences, Ponce, Puerto Rico

    Diana Morales

  2. NeuroAIDS Specialized Neuroscience Research Program, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico

    Rosa Hechavarria & Valerie Wojna

  3. Department of Physical Medicine and Rehabilitation, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico

    Rosa Hechavarria

  4. Neurology Division, Department of Internal Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico

    Valerie Wojna

  5. Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, 75235, USA

    Summer F. Acevedo

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  1. Diana Morales
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  2. Rosa Hechavarria
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  4. Summer F. Acevedo
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Correspondence to Summer F. Acevedo.

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Morales, D., Hechavarria, R., Wojna, V. et al. YWHAE/14-3-3ε: a potential novel genetic risk factor and CSF biomarker for HIV neurocognitive impairment. J. Neurovirol. 19, 471–478 (2013). https://doi.org/10.1007/s13365-013-0200-z

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  • DOI: https://doi.org/10.1007/s13365-013-0200-z

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