HIV-associated Encephalitis Research Articles

Pattern of TAAR5 Expression in the Human Brain Based on Transcriptome Datasets Analysis.

Trace amine-associated receptors (TAAR) recognize organic compounds, including primary, secondary, and tertiary amines. The TAAR5 receptor is known to be involved in the olfactory sensing of innate socially relevant odors encoded by volatile amines. However, emerging data point to the involvement of TAAR5 in brain functions, particularly in the emotional behaviors mediated by the limbic system which suggests its potential contribution to the pathogenesis of neuropsychiatric diseases. TAAR5 expression was explored in datasets available in the Gene Expression Omnibus, Allen Brain Atlas, and Human Protein Atlas databases. Transcriptomic data demonstrate ubiquitous low TAAR5 expression in the cortical and limbic brain areas, the amygdala and the hippocampus, the nucleus accumbens, the thalamus, the hypothalamus, the basal ganglia, the cerebellum, the substantia nigra, and the white matter. Altered TAAR5 expression is identified in Down syndrome, major depressive disorder, or HIV-associated encephalitis. Taken together, these data indicate that TAAR5 in humans is expressed not only in the olfactory system but also in certain brain structures, including the limbic regions receiving olfactory input and involved in critical brain functions. Thus, TAAR5 can potentially be involved in the pathogenesis of brain disorders and represents a valuable novel target for neuropsychopharmacology.

Exploration of the involvement of LncRNA in HIV-associated encephalitis using bioinformatics.

BackgroundHIV-associated encephalitis (HIVE) is one of the common complications of HIV infection, and the pathogenesis of HIVE remains unclear, while lncRNA might be involved it. In this study, we made re-annotation on the expression profiling from the HIVE study in the public database, identified the lncRNA that might be involved in HIVE, and explored the possible mechanism.MethodsIn the GEO public database, the microarray expression profile (GSE35864) of three regions of brain tissues (white matter, frontal cortex and basal ganglia brain tissues) was chosen, updated annotation was performed to construct the non-cording-RNA (ncRNA) microarray data. Morpheus was used to identify the differential expressed ncRNA, and Genbank of NCBI was used to identify lncRNAs. The StarBase, PITA and miRDB databases were used to predict the target miRNAs of lncRNA. The TargetScan, PicTar and MiRanda databases were used to predict the target genes of miRNAs. The GO and KEGG pathway analysis were used to make function analysis on the targets genes.ResultsSeventeen differentially expressed lncRNAs were observed in the white matter of brain tissues, for which 352 target miRNAs and 6,659 target genes were predicted. The GO function analysis indicated that the lncRNAs were mainly involved in the nuclear transcription and translation processes. The KEGG pathway analysis showed that the target genes were significantly enriched in 33 signal pathways, of which 11 were clearly related to the nervous system function.DiscussionThe brand-new and different microarray results can be obtained through the updated annotation of the chips, and it is feasible to identify lncRNAs from ordinary chips. The results suggest that lncRNA may be involved in the occurrence and development of HIVE, which provides a new direction for further research on the diagnosis and treatment of HIVE.

Gene expression profiles and protein-protein interaction network analysis in AIDS patients with HIV-associated encephalitis and dementia.

Central nervous system dysfunction is an important cause of morbidity and mortality in patients with human immunodeficiency virus type 1 (HIV-1) infection and acquired immunodeficiency virus syndrome (AIDS). Patients with AIDS are usually affected by HIV-associated encephalitis (HIVE) with viral replication limited to cells of monocyte origin. To examine the molecular mechanisms underlying HIVE-induced dementia, the GSE4755 Affymetrix data were obtained from the Gene Expression Omnibus database and the differentially expressed genes (DEGs) between the samples from AIDS patients with and without apparent features of HIVE-induced dementia were identified. In addition, protein–protein interaction networks were constructed by mapping DEGs into protein–protein interaction data to identify the pathways that these DEGs are involved in. The results revealed that the expression of 1,528 DEGs is mainly involved in the immune response, regulation of cell proliferation, cellular response to inflammation, signal transduction, and viral replication cycle. Heat-shock protein alpha, class A member 1 (HSP90AA1), and fibronectin 1 were detected as hub nodes with degree values >130. In conclusion, the results indicate that HSP90A and fibronectin 1 play important roles in HIVE pathogenesis.

Tenofovir and emtricitabine cerebrospinal fluid-to-plasma ratios correlate to the extent of blood-brainbarrier damage

Antiretroviral treatment is generally highly effective in controlling HIV replication in the central nervous system (CNS), although resistance associated mutations may be locally selected [1]. Drug passage into the CNS is known to be variable, being influenced by several parameters such as protein binding, molecular weight, lipophilicity, ionization, as well as by the presence of membrane transporters. According to a recently defined CNS drug penetration/effectiveness score, which was found to be associated to a significantly lower risk of viral replication in the cerebrospinal fluid (CSF), tenofovir and emtricitabine are classified as drugs with poor and good penetration, respectively [2]. However, a high interindividual variability of drug passage was recorded in pharmacokinetic studies. In this setting, the possible role of disrupted blood-brain barrier (BBB) deserves consideration, as altered BBB has been frequently reported in asymptomatic HIV-positive patients (2–22%) and in up to 100% of those with HIV-associated encephalitis [3,4]. In other neurological diseases [5], drug penetration into CSF is known to be significantly affected by disruption of BBB, but only limited evidence of this is available in case of HIV-infected patients receiving antiretroviral treatment [6]. We thus performed a pilot clinical study to investigate the effect of BBB disruption on tenofovir and emtricitabine passage into the CSF. HIV-positive patients under treatment with Truvada-containing regimens who underwent a lumbar puncture for clinical reasons after having signed an informed consent were enrolled. Plasma and CSF tenofovir and emtricitabine concentrations were measured through a validated high-performance liquid chromatography-mass spectrometry system with a limit of detection of 2 and 1.5 ng/ml, respectively [7]. Albumin and immunoglobulin G (IgG) were measured both in plasma and CSF and albumin and IgG ratios were calculated; the Reiber index was used to evaluate BBB disruption. Data are expressed in median (interquartile range); association between variables were determined by Spearman test through SPSS, version 18.0 (SPSS Inc., Chicago, Illinois, USA). Twenty-one patients were enrolled; 11 (52.4%) were men aged 38 (34–50) years old and presenting a BMI of 21.7 kg/m2 (20–24.3). Drugs other than Truvada were mostly boosted protease inhibitors (66.7%) followed by non-nucleoside reverse transcriptase inhibitors (28.5%). Lumbar punctures were mainly performed to investigate neurocognitive disorders (29%) and MRI abnormalities (14%) and to follow up opportunistic diseases (29%; non-Hodgkin's lymphomas, neurotoxoplasmosis and tubercular menigitis). BBB was altered in nine (42.8%) patients with albumin and IgG ratios, respectively, of 5.2 (4.7–8) and 5.4 (3.5–8). Plasma and CSF were sampled at different time points but within 15 min from each other; median time after drug intake was 15 h (13.8–19.4). Tenofovir and emtricitabine plasma concentrations were respectively 49 (29.5–114) and 212 ng/ml (86.5–445.5). Tenofovir (TDF) CSF median concentration was 6 ng/ml (<2–8), and a linear correlation with plasma concentrations (P = 0.018) emerged. TDF CSF-to-plasma ratio was 0.05 (0–0.13). Emtricitabine (FTC) CSF median concentration was 68 ng/ml (2.5–98), with a significant correlation to plasma concentrations (P = 0.02). FTC CSF-to-plasma ratio was 0.26 (0.05–0.41). A significant correlation between tenofovir and emtricitabine CSF-to-plasma ratios emerged (rho = 0.74, P = 0.002) (Fig. 1a). Both TDF and FTC ratios directly correlated to albumin ratios (respectively rho = 0.5 and P = 0.02, and rho = 0.05 and P = 0.05) (Fig. 1b and 1c); TDF ratios were correlated to IgG ratios (rho = 0.48, P = 0.03).Fig. 1: Scatter-dot plot of tenofovir, emtricitabine and albumin cerebrospinal fluid to plasma ratios.Tenofovir and emtricitabine (left), tenofovir and albumin (middle), emtricitabine and albumin (right) cerebrospinal fluid to plasma ratios. Trendlines are represented as dotted lines.Some limitations of our study should be pointed out; a limited sample size, heterogeneous clinical conditions and a single sample per patient could potentially impact on our results. Nevertheless, being BBB abnormalities common during the course of HIV infection and pharmacokinetics parameters widely variable, these observations could improve our knowledge on CNS penetration of antiretroviral drugs. In our patients, CSF-to-plasma ratios varied from 0–13% (for tenofovir) and from 5–41% (for emtricitabine), although median values were comparable to the ones reported in the literature [8,9]. The ratios of these two drugs with similar characteristics (high molecular weight and protein binding) were significantly correlated to each other, which suggest that the CSF penetration of both drugs can be influenced by common mechanisms and by alterations in the permeability of the BBB. Because both drugs seem to penetrate better in patients with altered BBB, we wonder whether barrier integrity should be considered as a factor potentially determining CNS concentrations. Barrier integrity might thus contribute to the high interindividual variability of drug penetration into the CNS. Our findings provide support to the recently suggested [10] correlation between altered albumin ratios and the prevalence of HIV-associated neurocognitive disorders in a cohort of HAART-treated individuals, although larger cohorts need to be studied before conclusive validation of this interpretation can be established.

The comorbidity of HIV-associated neurocognitive disorders and Alzheimer's disease: a foreseeable medical challenge in post-HAART era.

Although the introduction of highly active antiretroviral therapy (HAART) has led to a strong reduction of HIV-associated dementia (HAD) incidence, the prevalence of minor HIV-1-associated neurocognitive disorder (HAND) is rising among AIDS patients. HAART medication has shifted neuropathology from a subacute encephalitic condition to a subtle neurodegenerative process involving synaptic and dendritic degeneration, particularly of hippocampal neurons that are spared prior to HAART medication. Considerable neuroinflammation coupled with mononuclear phagocyte activation is present in HAART-medicated brains, particularly in the hippocampus. Accumulating evidence suggests that the resultant elevated secretion of pro-inflammatory cytokines such as interferon-gamma, tumor necrosis factor-alpha, and interleukin-1beta can increase amyloid-beta peptide (Abeta) generation and reduce Abeta clearance. Recent advancements in Alzheimer's disease (AD) research identified Abeta biogenesis and clearance venues that are potentially influenced by HIV viral infection, providing new insights into beta-amyloidosis segregation in HIV patients. Our study suggests enhanced beta-amyloidosis in ART-treated HAD and HIV-associated encephalitis brains and suppression of Abeta clearance by viral infection of human primary macrophages. A growing awareness of potential convergent mechanisms leading to neurodegeneration shared by HIV and Abeta points to a significant chance of comorbidity of AD and HAND in senile HIV patients, which calls for a need of basic studies.

Characterization of Cell Death Pathways in Human Immunodeficiency Virus-Associated Encephalitis

Human immunodeficiency virus (HIV)-associated dementia is a neurodegenerative syndrome characterized by cognitive decline, personality change, and motor deficits. HIV-associated encephalitis (HAE), the neuropathology responsible for HIV-associated dementia, involves the formation of multinucleated giant cells or syncytia. In this article we describe the apoptotic pathways activated in the brains of HAE-affected patients. Approximately 50% of multinuclear giant cells exhibited apoptotic DNA fragmentation as detected by the terminal dUTP nick-end labeling technique. In addition, the presence of syncytia in the frontal cortex of approximately 35% of HAE patients correlated with the number of cells expressing the HIV-1 protein p24. Histochemical and immunohistochemical analyses revealed that HAE-associated syncytia underwent apoptosis through a mitochondrial pathway previously delineated for HIV-1 envelope-elicited syncytia in vitro. We observed over-expression of the mammalian target of rapamycin (mTOR), a kinase that mediates activation of the pro-apoptotic transcription factor p53, and p53-dependent up-regulation of two effectors of mitochondrial apoptosis, namely the BH3-only proteins Puma and transglutaminase type 2 (TG2). Interestingly, although mTOR activation and Puma induction were observed in dying syncytia and neurons, IkB phosphorylation and TG2 up-regulation were only found in syncytia. These findings provide substantial new information on the cell death mechanisms that regulate HAE, suggesting an important pathogenetic role of syncytia in the disease.

Neurotrophic Actions of Mood-Stabilizers: A Recent Research Discovery and its Potential Clinical Applications

Recent in vitro and in vivo studies reveal that mood stabilizers lithium and valproate activate the extracellular signal-regulated kinase (ERK) pathway and the phosphoinositide 3-kinase (PI3K) pathways. The activations of the ERK and PI3K pathways are major signaling mechanisms by which neurotrophic factors modulate neurogenesis, neuronal growth and regeneration, neuronal survival, and synaptic plasticity. Like neurotrophic factors, lithium and valproate promote neurite outgrowth and axonal regeneration in cultured neuronal cells and in injury models utilizing retinal cells, sciatic nerve, and spinal cord. These mood stabilizers also enhance neurogenesis in cultured cortical and hippocampal cells and in the hippocampal dentate gyrus of adult animals. Treatments with these mood stabilizers protect cultured cells against a variety of insults and reduce neuronal loss and associated functional deficits in animal models of Alzheimers disease, HIV-associated encephalitis and dementia, Huntingtons disease, ischemia, and Parkinsons disease. Crosssectional and longitudinal brain imaging studies show that lithium treatment increases brain N-acetyl aspartate levels and cerebral gray matter volumes in patients with mood disorders. These data suggest that mood stabilizers and neurotrophins share common mechanisms of action that may contribute to their therapeutic effects.

Compartmentalization of HIV-1 in the central nervous system: role of the choroid plexus

To determine the genetic and phenotypic composition of HIV-1 found in the choroid plexus (CPx) and its relationship to virus in the brain and peripheral lymphoid tissue. Phenotypic and molecular comparisons of HIV-1 found in autopsy brain, CPx, and spleen tissues. HIV-1 was co-cultured from matched postmortem brain (basal ganglia), CPx, and spleen tissues of AIDS patients with and without HIV-associated encephalitis and dementia. Viral phenotypes were determined by infection of monocyte-derived macrophages, MT-2 or co-receptor-specific cell lines. Viral env and pol sequences were determined from genomic DNA isolated directly from tissues or co-cultures, and phylogenetic comparisons were performed. CCR5-utilization was the most prevalent viral tropism found in all tissues, although spleen isolates also displayed CXCR4 usage. Viruses isolated from CPx consisted of both peripheral and brain-like virus, but were more related phenotypically and genetically to those found in the brain. Mutations found in the pol gene that could confer drug resistance to brain and CPx isolates were similar to those found in the periphery. The CPx contained replication-competent virus that was most similar, although distinct, from that found in the brain. It also contained some viruses with high similarity to those of peripheral origin. Compartmentalization of viral env and pol sequences indicated that differential selective pressures exist in each tissue examined. These studies suggest that the CPx may provide an environment that promotes the evolution of drug-resistant strains with central nervous system tropism, although it is unlikely to be a reservoir for archival HIV-1 variants.