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Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV.
- Source :
-
Journal of neurovirology [J Neurovirol] 2016 Aug; Vol. 22 (4), pp. 431-41. Date of Electronic Publication: 2015 Dec 04. - Publication Year :
- 2016
-
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.
- Subjects :
- AIDS Dementia Complex genetics
AIDS Dementia Complex immunology
AIDS Dementia Complex virology
Adaptor Proteins, Signal Transducing genetics
Adaptor Proteins, Signal Transducing immunology
Adult
Amyloid beta-Peptides genetics
Amyloid beta-Peptides immunology
Biomarkers metabolism
Calcium-Binding Proteins
Chemokine CCL2 genetics
Chemokine CCL2 immunology
DNA-Binding Proteins genetics
DNA-Binding Proteins immunology
Female
Frontal Lobe immunology
Frontal Lobe pathology
Frontal Lobe virology
Gene Expression
Hippocampus immunology
Hippocampus pathology
Hippocampus virology
Humans
Interleukin-1alpha genetics
Interleukin-1alpha immunology
Male
Microfilament Proteins
Microtubule-Associated Proteins immunology
Middle Aged
Putamen immunology
Putamen pathology
Putamen virology
Receptors, Dopamine genetics
Receptors, Dopamine immunology
Severity of Illness Index
Synaptophysin immunology
Viral Load
AIDS Dementia Complex pathology
Microtubule-Associated Proteins genetics
Multilevel Analysis
Synaptophysin genetics
Virus Replication
Subjects
Details
- Language :
- English
- ISSN :
- 1538-2443
- Volume :
- 22
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of neurovirology
- Publication Type :
- Academic Journal
- Accession number :
- 26637429
- Full Text :
- https://doi.org/10.1007/s13365-015-0410-7