Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV

Andrew J. Levine, Virawudh Soontornniyomkij, Cristian L. Achim, Eliezer Masliah, Benjamin Gelman, Janet S. Sinsheimer, Elyse J. Singer, David J. Moore

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) remains puzzling. We interrogated several levels of data (host genetic, histopathology, brain viral load, and neurocognitive) to identify histopathological changes most relevant to HAND. The design of the study is a clinicopathological study employing genetic association analyses. Data and brain tissue from 80 HIV-infected adults were used. Markers in monocyte chemoattractant protein-1 (MCP-1), interleukin 1-alpha (IL1-α), macrophage inflammatory protein 1-alpha (MIP1-α), DRD3, DRD2, and apolipoprotein E (ApoE) were genotyped. Microtubule associated protein 2 (MAP2), synaptophysin (SYP), human leukocyte antigen-DR (HLA-DR), glial fibrillary acidic protein (GFAP), amyloid beta (A-Beta), and ionized calcium-binding adaptor molecule-1 (Iba-1) immunoreactivity were quantified in the frontal cortex, putamen, and hippocampus. A composite score for each marker (mean of the three brain regions) was used. Neurocognitive functioning and other clinical variables were determined within 1 year of death. Brain HIV RNA viral load was available for a subset of cases. MAP2 and SYP proved most relevant to neurocognitive functioning. Immunoreactivity of these markers, as well as A-Beta and Iba-1, was correlated with brain HIV RNA viral load. Several genetic markers in combination with other factors predicted histopathology: HIV blood viral load, MIP1-α genotype, and DRD3 genotype predicted Iba-1 immunoreactivity; the duration of infection and IL1-α genotype predicted GFAP immunoreactivity; ApoE genotype and age at death predicted A-Beta immunoreactivity. These data indicate that HIV replication in the brain is the primary driving force leading to neuroinflammation and dysfunctional protein clearance, as reflected by A-Beta and Iba-1. Downstream to these changes are synaptodendritic degeneration, which is the immediate histopathological substrate of the neurocognitive impairment characteristic of HAND. These intermediate histopathological phenotypes are influenced by host genetic polymorphisms in genes encoding cytokines/chemokines, neuronal protein clearance pathways, and dopaminergic factors.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalJournal of NeuroVirology
DOIs
StateAccepted/In press - Dec 4 2015

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Multilevel Analysis
HIV
Viral Load
Amyloid
Brain
Genotype
Chemokine CCL3
Calcium
Synaptophysin
Interleukin-1alpha
Microtubule-Associated Proteins
Glial Fibrillary Acidic Protein
Apolipoproteins E
RNA
Chemokine CCL2
Putamen
Genetic Association Studies
Frontal Lobe
Genetic Polymorphisms
HLA Antigens

Keywords

  • Histopathology
  • HIV
  • HIV-associated neurocognitive disorders
  • Host genetic
  • NeuroAIDS
  • Synaptodendritic

ASJC Scopus subject areas

  • Virology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Neurology

Cite this

Levine, A. J., Soontornniyomkij, V., Achim, C. L., Masliah, E., Gelman, B., Sinsheimer, J. S., ... Moore, D. J. (Accepted/In press). Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV. Journal of NeuroVirology, 1-11. https://doi.org/10.1007/s13365-015-0410-7

Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV. / Levine, Andrew J.; Soontornniyomkij, Virawudh; Achim, Cristian L.; Masliah, Eliezer; Gelman, Benjamin; Sinsheimer, Janet S.; Singer, Elyse J.; Moore, David J.

In: Journal of NeuroVirology, 04.12.2015, p. 1-11.

Research output: Contribution to journalArticle

Levine, AJ, Soontornniyomkij, V, Achim, CL, Masliah, E, Gelman, B, Sinsheimer, JS, Singer, EJ & Moore, DJ 2015, 'Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV', Journal of NeuroVirology, pp. 1-11. https://doi.org/10.1007/s13365-015-0410-7
Levine AJ, Soontornniyomkij V, Achim CL, Masliah E, Gelman B, Sinsheimer JS et al. Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV. Journal of NeuroVirology. 2015 Dec 4;1-11. https://doi.org/10.1007/s13365-015-0410-7
Levine, Andrew J. ; Soontornniyomkij, Virawudh ; Achim, Cristian L. ; Masliah, Eliezer ; Gelman, Benjamin ; Sinsheimer, Janet S. ; Singer, Elyse J. ; Moore, David J. / Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV. In: Journal of NeuroVirology. 2015 ; pp. 1-11.
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