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.
Subject(s)
AIDS Dementia Complex/pathology , Microtubule-Associated Proteins/genetics , Multilevel Analysis , Synaptophysin/genetics , Virus Replication , 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 LoadABSTRACT
We describe current research that applies epigenetics to a novel understanding of the immuno-neuropathogenesis of HIV-1 viral infection and NeuroAIDS. We propose the hypothesis that HIV-1 alters the structure-function relationship of chromatin, coding DNA and non-coding DNA, including RNA transcribed from these regions resulting in pathogenesis in AIDS, drug abuse, and NeuroAIDS. We discuss the general implications of molecular epigenetics with special emphasis on drug abuse, bar-codes, pyknons, and miRNAs for translational and clinical research. We discuss the application of the recent recursive algorithm of biology to this field and propose to synthesize the Genomic and Epigenomic views into a holistic approach of HoloGenomics.