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A candidate gene study of intermediate histopathological phenotypes in HIV-associated neurocognitive disorders

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A Correction to this article was published on 06 July 2020

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Abstract

HIV-associated neurocognitive disorders (HAND) describe a spectrum of neuropsychological impairment caused by HIV-1 infection. While the sequence of cellular and physiological events that lead to HAND remains obscure, it likely involves chronic neuroinflammation. Host genetic markers that increase the risk for HAND have been reported, but replication of such studies is lacking, possibly due to inconsistent application of a behavioral phenotype across studies. In the current study, we used histopathologic phenotypes in order to validate putative risk alleles for HAND. The National NeuroAIDS Tissue Consortium, a longitudinal study of the neurologic manifestations of HIV. Data and specimens were obtained from 175 HIV-infected adults. After determining several potential covariates of neurocognitive functioning, we quantified levels of six histopathological markers in the frontal lobe in association with neurocognitive functioning: SYP, MAP 2, HLA-DR, Iba1, GFAP, and β-amyloid. We then determined alleles of 15 candidate genes for their associations with neurocognitive functioning and histopathological markers. Finally, we identified the most plausible causal pathway based on our data using a multi-stage linear regression-based mediation analysis approach. None of the genetic markers were associated with neurocognitive functioning. Of the histopathological markers, only MAP 2 and SYP were associated with neurocognitive functioning; however, MAP 2 and SYP did not vary as a function of genotype. Mediation analysis suggests a causal pathway in which presynaptic degeneration (SYP) leads to somatodendritic degeneration (MAP 2) and ultimately neurocognitive impairment. This study did not support the role of host genotype in the histopathology underlying HAND. The findings lend further support for synaptodendritic degeneration as the proximal underlying neuropathological substrate of HAND.

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  • 06 July 2020

    Due to a production error data in Table 1 were not presented correctly.

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Funding

This study was financially supported by NIH funding (R01MH096648—Levine and Moore), along with shared resources from NIH funding through the NIMH and NINDS to the National NeuroAIDS Tissue Consortium (NNTC), which is supported through the following grants: Manhattan HIV Brain Bank—U24MH100931; Texas NeuroAIDS Research Center—U24MH100930; National Neurological AIDS Bank—U24MH100929; California NeuroAIDS Tissue Network—U24MH100928; Data Coordinating Center—U24MH100925.

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Authors and Affiliations

  1. Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA

    Andrew J. Levine & Elyse J. Singer

  2. Department of Psychiatry, University of California San Diego School of Medicine, San Diego, CA, USA

    Virawudh Soontornniyomkij & David J. Moore

  3. Departments of Neurosciences and Pathology, University of California San Diego School of Medicine, San Diego, CA, USA

    Eliezer Masliah

  4. Departments of Human Genetics and Computational Biology, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA

    Janet S. Sinsheimer

  5. Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA

    Janet S. Sinsheimer, Sarah S. Ji & Steve Horvath

  6. Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA

    Steve Horvath

  7. Department of Molecular Medicine, Genomic Medicine, Medicine, & Pediatrics, Cleveland Clinic/Lerner Research Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

    Asha Kallianpur

Authors
  1. Andrew J. Levine
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  2. Virawudh Soontornniyomkij
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  3. Eliezer Masliah
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  4. Janet S. Sinsheimer
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  5. Sarah S. Ji
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  6. Steve Horvath
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  7. Elyse J. Singer
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  8. Asha Kallianpur
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  9. David J. Moore
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Contributions

All authors contributed to the study conception, design, and/or execution. Andrew Levine and David Moore were involved in the initial study conception and design. Asha Kallianpur was involved in selecting genetic markers for the study. Data and specimen collection were performed or overseen by David Moore and Elyse Singer at their respective National NeuroAIDS Tissue Consortium sites. Tissue analysis was performed by Virawudh Soontornniyomkij and Eliezer Masliah. Data analysis was performed by Janet Sinsheimer, Sarah, Ji, Steve Horvath, and Andrew Levine. The first draft of the manuscript was written by Andrew Levine, David Moore, Virawudh Soontornniyomkij, Janet Sinsheimer, and Sarah Ji, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Andrew J. Levine.

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Levine, A.J., Soontornniyomkij, V., Masliah, E. et al. A candidate gene study of intermediate histopathological phenotypes in HIV-associated neurocognitive disorders. J. Neurovirol. 26, 496–508 (2020). https://doi.org/10.1007/s13365-020-00846-z

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  • DOI: https://doi.org/10.1007/s13365-020-00846-z

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