The National NeuroAIDS Tissue Consortium brain gene array: two types of HIV-associated neurocognitive impairment.
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 log(10) 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.


CONCLUSIONS
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).
Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA. bgelman@utmb.edu
Benjamin B
BB
Gelman
Tiansheng
T
Chen
Joshua G
JG
Lisinicchia
Vicki M
VM
Soukup
J Russ
JR
Carmical
Jonathan M
JM
Starkey
Eliezer
E
Masliah
Deborah L
DL
Commins
Dianne
D
Brandt
Igor
I
Grant
Elyse J
EJ
Singer
Andrew J
AJ
Levine
Jeremy
J
Miller
Jessica M
JM
Winkler
Howard S
HS
Fox
Bruce A
BA
Luxon
Susan
S
Morgello
D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D015658:HIV Infections / Q000503:physiopathology*; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D011956:Receptors, Cell Surface / Q000235:genetics; D019562:Viral Load; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D011956:Receptors, Cell Surface