The National NeuroAIDS Tissue Consortium Brain Gene Array

Two Types of HIV-Associated Neurocognitive Impairment

Benjamin Gelman, Tiansheng Chen, Joshua G. Lisinicchia, Vicki M. Soukup, J. Russ Carmical, Jonathan Starkey, Eliezer Masliah, Deborah L. Commins, Dianne Brandt, Igor Grant, Elyse J. Singer, Andrew J. Levine, Jeremy Miller, Jessica M. Winkler, Howard S. Fox, Bruce A. Luxon, Susan Morgello

Research output: Contribution to journalArticle

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Abstract

Background: The National NeuroAIDS Tissue Consortium (NNTC) performed a brain gene expression array to elucidate pathophysiologies of Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders. Methods: Twenty-four human subjects in four groups were examined A) Uninfected controls; B) HIV-1 infected subjects with no substantial neurocognitive impairment (NCI); C) Infected with substantial NCI without HIV encephalitis (HIVE); D) Infected with substantial NCI and HIVE. RNA from neocortex, white matter, and neostriatum was processed with the Affymetrix® array platform. Results: With HIVE the HIV-1 RNA load in brain tissue was three log10 units higher than other groups and over 1,900 gene probes were regulated. Interferon response genes (IFRGs), antigen presentation, complement components and CD163 antigen were strongly upregulated. In frontal neocortex downregulated neuronal pathways strongly dominated in HIVE, including GABA receptors, glutamate signaling, synaptic potentiation, axon guidance, clathrin-mediated endocytosis and 14-3-3 protein. Expression was completely different in neuropsychologically impaired subjects without HIVE. They had low brain HIV-1 loads, weak brain immune responses, lacked neuronally expressed changes in neocortex and exhibited upregulation of endothelial cell type transcripts. HIV-1-infected subjects with normal neuropsychological test results had upregulation of neuronal transcripts involved in synaptic transmission of neostriatal circuits. Interpretation: Two patterns of brain gene expression suggest that more than one pathophysiological process occurs in HIV-1-associated neurocognitive impairment. Expression in HIVE suggests that lowering brain HIV-1 replication might improve NCI, whereas NCI without HIVE may not respond in kind; array results suggest that modulation of transvascular signaling is a potentially promising approach. Striking brain regional differences highlighted the likely importance of circuit level disturbances in HIV/AIDS. In subjects without impairment regulation of genes that drive neostriatal synaptic plasticity reflects adaptation. The array provides an infusion of public resources including brain samples, clinicopathological data and correlative gene expression data for further exploration (http://www.nntc.org/gene-array-project).

Original languageEnglish (US)
Article numbere46178
JournalPLoS One
Volume7
Issue number9
DOIs
StatePublished - Sep 26 2012

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Encephalitis
encephalitis
Human immunodeficiency virus 1
Viruses
Brain
Genes
HIV-1
HIV
Tissue
brain
neocortex
Neocortex
genes
Gene expression
Gene Expression
gene expression
Up-Regulation
RNA
14-3-3 Proteins
Neostriatum

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Gelman, B., Chen, T., Lisinicchia, J. G., Soukup, V. M., Carmical, J. R., Starkey, J., ... Morgello, S. (2012). The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV-Associated Neurocognitive Impairment. PLoS One, 7(9), [e46178]. https://doi.org/10.1371/journal.pone.0046178

The National NeuroAIDS Tissue Consortium Brain Gene Array : Two Types of HIV-Associated Neurocognitive Impairment. / Gelman, Benjamin; Chen, Tiansheng; Lisinicchia, Joshua G.; Soukup, Vicki M.; Carmical, J. Russ; Starkey, Jonathan; Masliah, Eliezer; Commins, Deborah L.; Brandt, Dianne; Grant, Igor; Singer, Elyse J.; Levine, Andrew J.; Miller, Jeremy; Winkler, Jessica M.; Fox, Howard S.; Luxon, Bruce A.; Morgello, Susan.

In: PLoS One, Vol. 7, No. 9, e46178, 26.09.2012.

Research output: Contribution to journalArticle

Gelman, B, Chen, T, Lisinicchia, JG, Soukup, VM, Carmical, JR, Starkey, J, Masliah, E, Commins, DL, Brandt, D, Grant, I, Singer, EJ, Levine, AJ, Miller, J, Winkler, JM, Fox, HS, Luxon, BA & Morgello, S 2012, 'The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV-Associated Neurocognitive Impairment', PLoS One, vol. 7, no. 9, e46178. https://doi.org/10.1371/journal.pone.0046178
Gelman, Benjamin ; Chen, Tiansheng ; Lisinicchia, Joshua G. ; Soukup, Vicki M. ; Carmical, J. Russ ; Starkey, Jonathan ; Masliah, Eliezer ; Commins, Deborah L. ; Brandt, Dianne ; Grant, Igor ; Singer, Elyse J. ; Levine, Andrew J. ; Miller, Jeremy ; Winkler, Jessica M. ; Fox, Howard S. ; Luxon, Bruce A. ; Morgello, Susan. / The National NeuroAIDS Tissue Consortium Brain Gene Array : Two Types of HIV-Associated Neurocognitive Impairment. In: PLoS One. 2012 ; Vol. 7, No. 9.
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