Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal pathology in acquired immunodeficiency syndrome (AIDS) is of interest in relation to cognitive impairment in AIDS patients and from the broader perspective of the pathogenesis of neurodegeneration. Cortical dendritic spine loss has been described in patients with AIDS and the aim of this study was to test the hypothesis that similar pathology is present in cynomolgus macaques infected with simian immunodeficiency virus (SIV). These animals develop an AIDS-like illness, but multinucleated giant cell encephalitis is not a feature and CNS virus load is found to be very low. Four animals infected for 2.5-3 months and four infected for 2-3 years were compared with four controls. The Golgi-Cox technique was employed to demonstrate dendritic morphology in the frontal cortex and the diameter of apical dendrites, dendritic spine density and dendritic spine lengths were measured in layer V pyramidal cells. Immunohistochemistry for microtubule-associated protein-2 (MAP-2), MHC class II and glial fibrillary acidic protein (GFAP) was also performed. In infected animals there was progressive spine loss and atrophy of remaining spines with loss of MAP-2 immunoreactivity at late time points. No parallel increase in GFAP immunostaining or MHC-class II expression in microglial cells was seen. We conclude that progressive neuronal dendritic pathology is a feature of SIVmac251 infection of cynomolgus macaques and is apparent relatively early in disease. Furthermore, dendritic abnormalities occur in the absence of either multinucleated giant cell pathology or substantial CNS virus load.
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PMID:Progressive dendritic pathology in cynomolgus macaques infected with simian immunodeficiency virus. 1019 71

The tyramide signal amplification (TSA) method has recently been introduced to improve the detection sensitivity of immunohistochemistry. We present three examples of applying this method to immunofluorescence confocal laser microscopy: (1) single labeling for CD54 in frozen mouse brain tissue; (2) double labeling with two unconjugated primary antibodies raised in the same host species (human immunodeficiency virus type 1 p24 and CD68) in paraffin-biopsied human lymphoid tissue; and (3) triple labeling for brain-derived neurotrophic factor, glial fibrillary acidic protein, and HLA-DR in paraffin-autopsied human brain tissue. The TSA method, when properly optimized to individual tissues and primary antibodies, is an important tool for immunofluorescence microscopy. Furthermore, the TSA method and enzyme pretreatment can be complementary to achieve a high detection sensitivity, particularly in formalin-fixed paraffin-embedded archival tissues. Using multiple-label immunofluorescence confocal microscopy to characterize the cellular localization of antigens, the TSA method can be critical for double labeling with unconjugated primary antibodies raised in the same host species.
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PMID:Tyramide signal amplification method in multiple-label immunofluorescence confocal microscopy. 1049 Dec 75

The CXC chemokine gamma interferon (IFN-gamma)-inducible protein CXCL10/IP-10 is markedly elevated in cerebrospinal fluid and brain of individuals infected with human immunodeficiency virus type 1 (HIV-1) and is implicated in the pathogenesis of HIV-associated dementia (HAD). To explore the possible role of CXCL10/IP-10 in HAD, we examined the expression of this and other chemokines in the central nervous system (CNS) of transgenic mice with astrocyte-targeted expression of HIV gp120 under the control of the glial fibrillary acidic protein (GFAP) promoter, a murine model for HIV-1 encephalopathy. Compared with wild-type controls, CNS expression of the CC chemokine gene CCL2/MCP-1 and the CXC chemokine genes CXCL10/IP-10 and CXCL9/Mig was induced in the GFAP-HIV gp120 mice. CXCL10/IP-10 RNA expression was increased most and overlapped the expression of the transgene-encoded HIV gp120 gene. Astrocytes and to a lesser extent microglia were identified as the major cellular sites for CXCL10/IP-10 gene expression. There was no detectable expression of any class of IFN or their responsive genes. In astrocyte cultures, soluble recombinant HIV gp120 protein was capable of directly inducing CXCL10/IP-10 gene expression a process that was independent of STAT1. These findings highlight a novel IFN- and STAT1-independent mechanism for the regulation of CXCL10/IP-10 expression and directly link expression of HIV gp120 to the induction of CXCL10/IP-10 that is found in HIV infection of the CNS. Finally, one function of IP-10 expression may be the recruitment of leukocytes to the CNS, since the brain of GFAP-HIV gp120 mice had increased numbers of CD3(+) T cells that were found in close proximity to sites of CXCL10/IP-10 RNA expression.
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PMID:Interferon-independent, human immunodeficiency virus type 1 gp120-mediated induction of CXCL10/IP-10 gene expression by astrocytes in vivo and in vitro. 1143 87

Macrophage chemoattractant protein-1 (MCP-1) may be a key trigger for the influx of macrophages into the brain in human immunodeficiency virus (HIV) encephalitis. In this study, simian immunodeficiency virus-infected macaques that developed moderate-to-severe encephalitis had significantly higher MCP-1 levels in cerebrospinal fluid (CSF) than in plasma as early as 28 days after inoculation, which was before the development of brain lesions. In contrast, CSF:plasma MCP-1 ratios remained constant at preinoculation levels in macaques that developed minimal or no encephalitis. Abundant MCP-1 protein and mRNA were detected in both macrophages and astrocytes in the brain. Macaques with increased MCP-1 in CSF had significantly greater expression of markers of macrophage and microglia activation and infiltration (CD68; P= .003) and astrocyte activation (glial fibrillary acidic protein; P= .019 and P= .031 in white and gray matter, respectively). The results suggest that the CSF:plasma MCP-1 ratio may be a valuable prognostic marker for the development of HIV-induced central nervous system disease.
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PMID:Increased macrophage chemoattractant protein-1 in cerebrospinal fluid precedes and predicts simian immunodeficiency virus encephalitis. 1157 16

Neural progenitor cells may provide for cell replacement or gene delivery vehicles in neurodegen-erative disease therapies. The expression of therapeutic proteins by neural progenitors would be enhanced by viral-mediated gene transfer, but the effects of several common recombinant viruses on primary progenitor cell populations have not been tested. To address this issue, we cultured cells from embryonic day 16-18 mouse brain in serum-free medium containing epidermal growth factor or basic fibroblast growth factor, and investigated how transduction with recombinant viral vectors affected maintenance and differentiation properties of progenitor cells. Neurosphere cultures were incubated with feline immunodeficiency virus (FIV), adeno-associated virus (AAV) or ade-noviral (Ad) constructs expressing either beta-galactosidase or enhanced green fluorescent protein at low multiplicity of infection. Nestin-positive neurospheres were regenerated after incubation of single progenitor cells with FIV, indicating that FIV-mediated gene transfer did not inhibit progenitor cell self-renewal. In contrast, adenovirus induced differentiation into glial fibrillary acidic protein (GFAP)-positive astrocytes. The AAV serotypes tested did not effectively transduce progenitor cells. FIV-transduced progenitors retained the potential for differentiation into neurons and glia in vitro, and when transplanted into the striatum of normal adult C57BL/6 mice differentiated into glia, or remained undifferentiated. In the presence of tumor cells, FIV-transduced progenitors migrated significantly from the injection site. Our results suggest that FIV-based vectors can transduce progenitor cell populations in vitro, with maintenance of their ability to differentiate into multiple cell types or to respond to injury within the central nervous system. These results hold promise for the use of genetically manipulated stem cells for CNS therapies.
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PMID:Viral-mediated gene transfer to mouse primary neural progenitor cells. 1178 41

HIV-1 infection is often complicated by the dysfunction of central nervous system (CNS). Degenerative neuronal changes as well as neuronal loss have been documented in individuals with acquired immunodeficiency syndrome. Feline immunodeficiency virus (FIV) causes similar CNS manifestation and FIV infected cats provide an animal model for human immunodeficiency virus infection in humans. In this study, we examined the brain of FIV-infected cats and controls with immunohistochemical techniques using antibodies to microtubule-associated protein 2 (MAP-2) and glutamic acid decarboxylase (GAD). We found a significant decrease in expression of MAP-2 and GAD in neurons of infected animals compared to controls. In contrast, the expression of neurofilaments and glial fibrillary acidic protein was rather increased. The changes observed in the brain were similar to those seen in humans undergoing the normal aging process as well as those suffering from neurological diseases like Alzheimer's disease and other dementing disorders. These changes in the feline brain give insight into the deleterious effects of FIV on the CNS.
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PMID:Decreased expression of MAP-2 and GAD in the brain of cats infected with feline immunodeficiency virus. 1187 47

Peripherin is a member of the type III intermediate filament family, expressed in neurones of the peripheral nervous system of many species and in a discrete subpopulation of neurones of the central nervous system (CNS) during early development in rodents. Previous studies on rats have shown that peripherin immunoreactivity increased significantly in cell bodies of spinal motor neurones following axonal injury. Our study examined the expression of peripherin in the cerebrum of normal macaques (Macaca mulatta and Macaca fascicularis) and those with encephalitis of viral (simian immunodeficiency virus and simian virus 40) or autoimmune (experimental allergic encephalomyelitis) aetiology. Immunohistochemistry, immunoelectronmicroscopy, immunofluorescence and confocal microscopy were performed on tissue sections using antibodies against cell-specific markers and peripherin. Peripherin-positive cells were absent in the cerebrum of normal macaques of all ages examined, whereas animals with encephalitis had peripherin-positive cells associated with inflammatory infiltrates. Further evaluation revealed that these peripherin-positive cells were not neurones, but were predominantly astrocytes expressing glial fibrillary acidic protein. Our study suggests that peripherin is not neurone-specific in the CNS of macaques; peripherin is expressed in astrocytes of animals with encephalitis.
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PMID:Expression of peripherin in the brain of macaques (Macaca mulatta and Macaca fascicularis) occurs in astrocytes rather than neurones and is associated with encephalitis. 1190 26

Several studies have shown that deletion of the nef gene of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) results in attenuated viruses. However, studies have not critically examined trafficking of attenuated viruses to the central nervous system (CNS) at early stages after inoculation. In this study, we investigated the colocalization of pathogenic and vpu-negative, nef-interrupted SHIVs at early stages following inoculation. The first virus, designated SHIV(50OLNV), was isolated from the lymph node of a pig-tailed macaque which developed severe CD4+ T cell loss and neurological disease. The second virus was a molecularly cloned virus in which the vpu gene was deleted and the gene for the enhanced green fluorescent protein from the jellyfish Aequoria victora had been inserted in-frame within the nef gene of the pathogenic SHIV(KU-1bMC33) (designated SHIV(KU-1bEGFP)). Three pig-tailed macaques were inoculated intravenously with equivalent amounts of two viruses, two macaques were inoculated with SHIV(KU-1bEGFP), and two macaques were inoculated with SHIV(50OLNV). The peripheral blood mononuclear cells (PBMCs) were isolated from bleeds obtained 3, 7, 10, and 14 days postinoculation and monitored for syncytia-inducing virus and for fluorescent cells. Virus was detected in the PBMCs as early as 3 days postinoculation and was present throughout the course of this short-term study. At 14 days postinoculation, the macaques were sacrificed and examined for virus in lymphoid tissues and different regions of the CNS following necropsy. Our results revealed the presence of both viruses in lymphoid and CNS tissues, although SHIV(50OLNV) was present to a much greater extent. Histological examination revealed that one macaque displayed signs of meningitis and all three macaques developed massive cortical astrocyte activation as demonstrated by immunostaining for glial fibrillary acidic protein, but only limited microglial activation. In the two macaques inoculated with SHIV(50OLNV), astrocyte activation similar to that in the macaques inoculated with both viruses was observed while no astrocyte activation was observed in macaques inoculated with SHIV(KU-1bEGFP). Thus, this study demonstrates that SHIVs with an intact nef(SHIV(50OLNV)) as well as those lacking a vpu gene and with a nonfunctional nef gene (SHIV(KU-1bEGFP)) are capable of invading the CNS and that pathogenic SHIVs are capable of causing reactive astrocytosis early after inoculation.
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PMID:Pathogenic and nef-interrupted simian-human immunodeficiency viruses traffic to the macaque CNS and cause astrocytosis early after inoculation. 1203 16

Measurement of central nervous system (CNS) expression of the peripheral benzodiazepine receptor (PBR), a microglia and macrophage activation marker, by positron emission tomography (PET) would aid clinical management of human immunodeficiency virus (HIV)-infected patients. To evaluate the utility of examining PBR expression in the CNS as a cellular activation marker in HIV CNS disease, PBR levels were measured in frontal cortex of simian immunodeficiency virus (SIV)-infected macaques with encephalitis and uninfected animals via PK11195 ligand autoradiography. [(3)H]-(R)-PK11195 binding to both grey matter (P =.017) and white matter (P =.038) was significantly higher in animals with SIV encephalitis (n = 10) versus control animals (n = 3). When PK11195 binding was compared with other microglial/macrophage activation markers (obtained via quantitative image analysis), a strong, significant association was found for both HAM56 (P =.004) and KP-1 (anti-CD68; P =.006) immunostaining in white matter. In contrast, grey matter PK11195 binding did not correlate with HAM56 (P =.46), KP-1 (P =.06), or glial fibrillary acidic protein (GFAP) immunostaining for astrocytic activation (P =.09). The regional nature of these increases in activation within the brain illustrates the crucial need to focus functional neuroimaging analyses of HIV-infected individuals on subcortical white matter to assess activation of microglia and macrophages.
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PMID:Elevated peripheral benzodiazepine receptor expression in simian immunodeficiency virus encephalitis. 1258 72

The human immunodeficiency virus type 1 (HIV-1) Tat protein is a key pathogenic factor in a variety of acquired immune deficiency syndrome (AIDS)-associated disorders. A number of studies have documented the neurotoxic property of Tat protein, and Tat has therefore been proposed to contribute to AIDS-associated neurological diseases. Nevertheless, the bulk of these studies are performed in in vitro neuronal cultures without taking into account the intricate cell-cell interaction in the brain, or by injection of recombinant Tat protein into the brain, which may cause secondary stress or damage to the brain. To gain a better understanding of the roles of Tat protein in HIV-1 neuropathogenesis, we attempted to establish a transgenic mouse model in which Tat expression was regulated by both the astrocyte-specific glial fibrillary acidic protein promoter and a doxycycline (Dox)-inducible promoter. In the present study, we characterized the phenotypic and neuropathogenic features of these mice. Both in vitro and in vivo assays confirmed that Tat expression occurred exclusively in astrocytes and was Dox-dependent. Tat expression in the brain caused failure to thrive, hunched gesture, tremor, ataxia, and slow cognitive and motor movement, seizures, and premature death. Neuropathologies of these mice were characterized by breakdown of cerebellum and cortex, brain edema, astrocytosis, degeneration of neuronal dendrites, neuronal apoptosis, and increased infiltration of activated monocytes and T lymphocytes. These results together demonstrate that Tat expression in the absence of HIV-1 infection is sufficient to cause neuropathologies similar to most of those noted in the brain of AIDS patients, and provide the first evidence in the context of a whole organism to support a critical role of Tat protein in HIV-1 neuropathogenesis. More importantly, our data suggest that the Dox inducible, brain-targeted Tat transgenic mice offer an in vivo model for delineating the molecular mechanisms of Tat neurotoxicity and for developing therapeutic strategies for treating HIV-associated neurological disorders.
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PMID:Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline. 1270 54


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