Abstract
BackgroundThe 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.MethodsTwenty-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.ResultsWith 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.InterpretationTwo 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).
Highlights
The worldwide pandemic of Human Immunodeficiency Virus type 1 (HIV-1) infection began in the early 1980s
HIV Loads and Human Brain RNA Isolates Three HIV-1 infected (HIV+) groups of subjects were compared to normal HIV negative (HIV-) controls (Table 1)
Subjects with Neurocognitive impairment (NCI) and HIV encephalitis (HIVE) (Group D) had brain HIV RNA loads averaging over three log10 units higher than those without HIVE (Groups B and C) similar to another report [27]
Summary
The worldwide pandemic of Human Immunodeficiency Virus type 1 (HIV-1) infection began in the early 1980s. Neurocognitive impairment (NCI) occurred most often in people with end-stage Acquired Immunodeficiency Syndrome (AIDS). The most severe form of neurocognitive impairment became recognized as the AIDS dementia complex, and later as HIV-associated dementia (HAD). The prevalence of HIVE in autopsy surveys did not decline as sharply because the population of decedents is skewed to those at the end-stages [5,6,7]. In recent times up to half of subjects in well-studied populations treated with HAART still exhibit milder impairments, which was nosologically renamed HIV-associated neurocognitive disorders (HAND) in 2007 [11]. 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
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