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Review

Editorial neuroAIDS review

Paul Shapshak et al. AIDS. .
No abstract available

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Figures

Fig. 1
Fig. 1. Amyloid-containing plaques (arrows) in the frontal cortex of a demented 69-year-old HIV-1-positive woman
Clinically, HIV-associated neurocognitive disorder was only one factor contributing to her dementia. At death, her brain contained numerous amyloid plaques and tau-neurofibrillary tangles (not shown), typical of AD (modified Bielschowsky silver stain, bar equals 250 μm). AD, Alzheimer's disease.
Fig. 2
Fig. 2. Blood–brain barrier in NeuroAIDS
(a) Blood–brain barrier (BBB) prior to infection. Normally, the human BBB, which is composed of interacting adjacent cerebral endothelial cells (CECs) and astrocytes, effectively separates the CNS from cellular and molecular components of the peripheral circulation and creates a unique reservoir environment for functioning neurons and astrocytes among other cells in the brain. Adjacent CECs contain tight junctions (TJs) that serve as the anatomic and functional barrier against harmful molecules from the blood stream. The process of transendothelial migration of HIV-1-infected monocytes involves interactions among adhesion molecules on CECs [e.g. vascular endothelial adhesion molecule (VCAM)] and their ligands on the activated leukocyte [very late antigen-4 (VLA-4)]. During the course of NeuroAIDS, HIV-1-infected macrophage/monocytes from the blood, traverse the TJs of the CECs and infiltrate the brain parenchyma. Once within this milieu, they differentiate into macrophage/microglia (MΦ). Drugs including cocaine and methamphetamine damage the BBB and further facilitate ingress of the HIV-1-infected monocytes into the brain. (b) BBB postinfection. Once within the brain parenchyma, HIV-1-infected MΦ secrete elevated levels of pro-inflammatory cytokines including interleukin-β (IL-β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), which in turn activate uninfected macrophage/microglia and adversely affect astrocytes. These pro-inflammatory cytokines also increase BBB permeability and induce further expression of adhesion molecules including VCAM and inter-cellular adhesion molecule (ICAM) by activated CECs, which in turn promote further ingress of HIV-1-infected monocytes into the CNS. In addition to cytokines, inflammatory chemokines contribute to brain inflammation [e.g. chemokine ligand 2 (CCL2); chemokine ligand 7 (CCL7); C-X-C motif chemokine 5 (CXCL5)]. Within the CNS, MFs produce nitric oxide (NO) and promote oxidative injury that affects both astrocytes and CECs. HIV-1-infected MΦs also release HIV-1 Tat protein that induces expression of the adhesion molecules by CECs. Neuronal injury in the context of NeuroAIDS is also promoted by processes including the activation of the N-methyl-D-aspartate receptor (NMDAR)-coupled ion channels, which in turn leads to massive influx of Ca+2 ions. This process then leads to activation of several enzymes including matrix metallo-proteinases, generation of free radicals, and release of glutamate, which cause neuronal apoptosis. Other inflammatory mediators such as platelet activating factor (PAF), arachidonate, and quinolinate (an NMDA agonist) also participate in neuronal injury. HIV-1 infection of astrocytes also leads to astroglyosis and inflammatory cascades. Reproduced with permission from [,,–189].
Fig. 3
Fig. 3. HLA structures (class I and II) superimposed with peptides in complex form using a set of known HLA-peptide structures determined by X-ray crystallography
The illustration shows structural features of superimposed multiple short peptides binding to HLA molecules, which is a prerequisite to stimulate T-cell immunity. HLA molecules are often polymorphic across ethnic groups and hence peptide binding specificity varies for each population. Reproduced with permission from [199].
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