Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV.

TitleMultilevel analysis of neuropathogenesis of neurocognitive impairment in HIV.
Publication TypeJournal Article
Year of Publication2016
AuthorsLevine, AJ, Soontornniyomkij, V, Achim, CL, Masliah, E, Gelman, BB, Sinsheimer, JS, Singer, EJ, Moore, DJ
JournalJ Neurovirol
Date Published2016 08
KeywordsAdaptor Proteins, Signal Transducing, Adult, AIDS Dementia Complex, Amyloid beta-Peptides, Biomarkers, Calcium-Binding Proteins, Chemokine CCL2, DNA-Binding Proteins, Female, Frontal Lobe, Gene Expression, Hippocampus, Humans, Interleukin-1alpha, Internal, Male, Microfilament Proteins, Microtubule-Associated Proteins, Middle Aged, Multilevel Analysis, Putamen, Receptors, Dopamine, Severity of Illness Index, Synaptophysin, Viral Load, Virus Replication

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.

Alternate JournalJ Neurovirol
PubMed ID26637429
PubMed Central IDPMC4893344
Grant ListU24 MH100929 / MH / NIMH NIH HHS / United States
U01 MH083500 / MH / NIMH NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States
R24 MH059745 / MH / NIMH NIH HHS / United States
R24 NS038841 / NS / NINDS NIH HHS / United States
R01 MH096648 / MH / NIMH NIH HHS / United States
N01 MH032002 / MH / NIMH NIH HHS / United States
P41 RR013642 / RR / NCRR NIH HHS / United States
P30 MH062512 / MH / NIMH NIH HHS / United States
U24 MH100930 / MH / NIMH NIH HHS / United States
R01 GM053275 / GM / NIGMS NIH HHS / United States