Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Previous neuropathological and morphometric studies of the cerebral cortex of patients with human immunodeficiency virus encephalitis (HIVE) have shown a decrease in the population of large neurons, moderate loss in synaptophysin immunoreactivity, and pathological changes in dendrites. To further characterize and quantify alterations in the dendritic tree of neocortical pyramidal neurons, we performed a modified Golgi impregnation technique on Formalin fixed blocks from the frontal cortex of 5 HIVE cases, 5 human immunodeficiency virus seropositive control cases without encephalitis, and 5 human immunodeficiency virus seronegative controls. Apical dendrites of HIVE cases were dilated, vacuolated, and tortuous with decreased length and branching. Basal and oblique dendrites also showed these alterations, but to a lesser extent. Some dendrites presented lacunae and filopodia consistent with remodeling. Computer aided quantification of HIVE cases showed a 40-60% decrease in spine density throughout the entire length of dendrites. Laser confocal imaging of Golgi impregnated sections displayed aberrant spines in regions of abnormal second order dendritic branches. These observations support the role of primary dendritic damage in HIVE in contrast to other neurodegenerative disorders where the primary pathology is presynaptic.
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PMID:Cortical dendritic pathology in human immunodeficiency virus encephalitis. 153 82

Central nervous system (CNS) damage occurs during retroviral infection in both man and animals. As a model of human disease, we studied the distribution and extent of CNS damage during retroviral infection with two molecularly cloned, neurotropic murine leukemia viruses. Both viruses mediate a spongiform encephalopathy involving predominantly the brainstem and spinal cord. During the course of disease, immune reactivity for synaptophysin (SYN) (to identify presynaptic elements) and microtubule-associated protein-2 (MAP-2) (to identify postsynaptic elements) were quantified using confocal laser microscopy. Immunostaining of SYN in the cerebral cortex (an area not exhibiting spongiform lesions) was similar in viral infected and age-matched control mice. However, compared to age matched controls, SYN staining in the brainstem (an area exhibiting spongiform lesions) of viral infected mice progressively declined during the course of disease. Quantitative analysis showed greater reduction of MAP-2 immunostaining in viral-infected mice compared to age-matched controls. In infected mice, both regions with and without spongiform lesions showed diminished MAP-2 staining. Widely distributed microscopic vacuolation of dendritic processes was observed in confocal preparations. These findings suggest primary dendritic damage in murine retroviral infection of the CNS similar to what has been described in human immunodeficiency virus-1 encephalitis.
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PMID:Synaptic and dendritic pathology in murine retroviral encephalitis. 828 27

Specific pathogen-free cats experimentally infected with feline immunodeficiency virus (FIV) were used to evaluate the development of central nervous system changes during the asymptomatic stages of viral infection. The brains of asyptomatic cats were examined at postinoculation times ranging from 8 weeks to 3 years for changes in neuron density, glutamate receptor density, and synaptophysin immunoreactivity. At 2-3 years postinoculation a small decrease in neuronal density was found in layers 2-3 and layer 5 of the frontal cortex (-14.4%), parietal cortex (-18.1%), and striatum (-29.5%). The only other indications of pathology within these regions were a mild diffuse astrogliosis, occasional microglial nodules, and the accumulation of satellite cells around selected neurons. An average loss of large neurons of 56-68% was seen in the cortex of four random source cats euthanized with AIDS. These values contrasted with the absence of any significant cell loss in FIV-infected cats 18 weeks after inoculation or FIV-negative controls. The loss of neurons in the asymptomatic cats showed a significant positive correlation with a decrease in the blood CD4:CD8 ratios. Morphometric evaluation of synaptic terminal densities immunocytochemically stained with synaptophysin revealed a significant increase in the asymptomatic cats at 2-3 years postinoculation that correlated negatively with the CD4:CD8 ratios. Random source AIDS cats showed a 34% decrease in synaptophysin-immunoreactive profiles. Glutamate binding in the cortex did not change significantly in the asymptomatic cats (4-7% decline). Thus, experimentally infected specific pathogen-free cats show a loss of cortical neurons similar to what has been observed in postmortem studies of humans infected with HIV. The detection of neuronal loss during the asymptomatic stage of disease and the correlation with the peripheral CD4:CD8 cell ratios indicate that neurodegeneration may progress in parallel with peripheral disease.
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PMID:Cortical cell loss in asymptomatic cats experimentally infected with feline immunodeficiency virus. 928 18

Polyomaviruses have proven oncogenicity in nonhost experimental animals; however, studies concerning the association between human brain tumors and simian and human polyomaviruses have yielded inconclusive results. We examined the relationship of SV40 to a malignant astrocytoma found in the right frontal lobe of a pigtail macaque (Macaca nemestrina) infected with simian immunodeficiency virus (SIV). Consistent with the histologic diagnosis, the tumor was immunoreactive with antibodies to S-100 protein, vimentin, and glial fibrillary acidic protein, but negative for neurofilament protein, synaptophysin, neuron-specific enolase, and chromogranin A. At the time of SIV inoculation, the animal was seropositive for SV40. Polymerase chain reaction assay of tumor DNA, but not normal brain DNA, yielded a 300 base-pair fragment corresponding to the carboxy-terminal coding region (C-terminus) of the large T antigen gene of SV40, suggesting an association with the tumor.
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PMID:A malignant astrocytoma containing simian virus 40 DNA in a macaque infected with simian immunodeficiency virus. 937 84

Mice infected with LP-BM5 develop a severe immunodeficiency accompanied by learning and memory deficits, gliosis, and neurotransmitter abnormalities. The neurochemical alterations are consistent with elevated excitotoxin levels, suggesting that infected mice may incur neuronal damage. Although the number of neocortical neurons was unchanged in mice 12 wk after LP-BM5 infection, the expression of cytoskeletal proteins declined, particularly in the frontal and parietal cortex as indicated by MAP2, NF-200, and synaptophysin immunoreactivity. In contrast, the number of striatal neurons decreased 19%. The remaining neurons were smaller, with fewer synaptic boutons, and showed decreased synaptophysin and NF-200, immunoreactivity. Immunoblots of cortex and striatum confirmed decreases in MAP2, NF-200 and synaptophysin expression. Finally, although NCAM expression decreased in the striatum, it increased in the cortex. These results indicate that LP-BM5-infected mice sustain significant neuronal damage, which may contribute to their behavioral deficits. Moreover, the increase in cortical NCAM expression suggests active synaptic remodeling to compensate for the persistent excitotoxic environment in these mice, whereas striatal neurons degenerate. These concurrent degenerative and compensatory processes may also occur in the brains of patients with AIDS dementia complex (ADC), who suffer extensive degeneration of the basal ganglia and cerebral cortex.
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PMID:Evidence of neuronal degeneration in C57B1/6 mice infected with the LP-BM5 leukemia retrovirus mixture. 1034 70

Neurodegeneration observed in lentiviral-associated encephalitis has been linked to viral-infected and -activated central nervous system macrophages. We hypothesized that lentivirus, macrophages, or both lentivirus and macrophages within distinct microenvironments mediate synaptic damage. Using the simian immunodeficiency virus (SIV)-infected macaque model, we assessed the relationship between virus, macrophages, and neurological damage in multiple brain regions using laser confocal microscopy. In SIV-infected macaques with SIV encephalitis (SIVE), brain tissue concentrations of SIV RNA were 5 orders of magnitude greater than that observed in nonencephalitic animals. In SIVE, staining for postsynaptic protein microtubule-associated protein-2 was significantly decreased in the caudate, hippocampus, and frontal cortical gray matter compared to nonencephalitic controls, whereas staining for presynaptic protein synaptophysin was decreased in SIV-infected macaques with and without encephalitis. These data suggest that presynaptic damage occurs independent of pathological changes associated with SIVE, whereas postsynaptic damage is more tightly linked to regional presence of both activated and infected macrophages.
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PMID:Macrophages relate presynaptic and postsynaptic damage in simian immunodeficiency virus encephalitis. 1189 Nov 91

Injection of human immunodeficiency virus type 1 (HIV-1)-infected human monocyte-derived macrophages (MDMs) into the basal ganglia of severe combined immunodeficient mice recapitulates histopathologic features of HIV-1 encephalitis (HIVE). Here, we show that the neural damage in HIVE mice extends beyond the basal ganglia and is associated with cognitive impairment. Morris water maze tests showed impaired spatial learning 8 d after MDM injection. Moreover, impaired synaptic potentiation in the hippocampal CA1 subregion was demonstrated at 8 and 15 d. By day 15, post-tetanic, short-term, and long-term potentiation were reduced by 14.1, 29.5, and 45.3% in HIVE mice compared with sham-injected or control animals. Neurofilament (NF) and synaptophysin (SP) antigens were decreased significantly in the CA2 hippocampal subregion of HIVE mice with limited neuronal apoptosis. By day 15, the CA2 region of HIVE mice expressed 3.8- and 2.6-fold less NF and SP than shams. These findings support the notion that HIV-1-infected and immune-competent brain macrophages can cause neuronal damage at distant anatomic sites. Importantly, the findings demonstrate the value of the model in exploring the physiological basis and therapeutic potential for HIV-1-associated dementia.
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PMID:Impaired spatial cognition and synaptic potentiation in a murine model of human immunodeficiency virus type 1 encephalitis. 1189 49

Patients with human immunodeficiency virus infection may develop a dementing illness. Using both in vitro and in vivo models, we investigated the susceptibility of the hippocampal formation to the Tat protein of human immunodeficiency virus. We also determined the pattern of hippocampal injury in patients with human immunodeficiency virus encephalitis. Following exposure of hippocampal slices to Tat, marked susceptibility of CA3 region with relative insensitivity of the CA1/2 region was observed. Injection of Tat into different regions of the rat hippocampus produced similar neuronal loss in both CA3 region and the dentate gyrus. In animals administered Tat, lesions were dose-dependent and immunohistochemical staining showed marked gliosis and loss of microtubule associated protein-2 in the affected areas at 3 days post-injection. Interestingly, synaptophysin staining was relatively preserved. In hippocampal tissue from patients with human immunodeficiency virus encephalitis, loss of microtubule-associated protein-2 staining was reduced in the molecular layer of the dentate gyrus. The results of our experiments demonstrate a unique pattern of hippocampal injury in organotypic culture and rats exposed to Tat. Our observations that patients with human immunodeficiency virus reveal a similar pattern of damage suggests that Tat protein may be pathophysiological relevant in human immunodeficiency virus encephalitis.
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PMID:Neuronal injury in hippocampus with human immunodeficiency virus transactivating protein, Tat. 1260 91

Two neuropathological changes that are linked with biological and pathological aging were examined in subjects with end-stage acquired immunodeficiency syndrome (AIDS). Autopsy brain specimens were examined from 25 people who died from complications of AIDS and 25 comparison subjects who were human immunodeficiency virus (HIV)-negative, matched for age, gender, ethnicity, and postmortem time interval. These adults were stratified into three age groups: elderly (62 to 75 years), intermediate (55 to 60 years), and young (21 to 42 years). Ubiquitin-stained dotlike deposits (Ub-dots) and diffuse extracellular plaques containing the beta-amyloid (Abeta) fragment of the amyloid precursor protein (Abeta plaque) were both increased significantly in the hippocampal formation of older subjects. In subjects with AIDS, Ub-dots were increased whereas Abeta plaque counts were not significantly different. Western blotting confirmed that high-molecular-weight ubiquitin-protein conjugates (HMW-Ub-conj) were increased in AIDS. The band intensity of one HMW-Ub-conj species with an approximate molecular mass of 145 kDa was correlated significantly with increased acute phase inflammatory protein (a-1-antichymotrypsin) and decreased synaptophysin and growth-associated protein-43 band intensities. These results raise the possibility that HIV-related brain inflammation disturbs neuronal protein turnover through the ubiquitin-proteasome apparatus, and might increase the prevalence of age-associated neurodegenerative diseases by decreasing synaptic protein turnover through the proteasome.
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PMID:Brain aging in acquired immunodeficiency syndrome: increased ubiquitin-protein conjugate is correlated with decreased synaptic protein but not amyloid plaque accumulation. 1520 28

HIV infection of the immature nervous system generally results in a rapid progression of neurological disease that cannot easily be explained by the severity of encephalitis, viral burden, systemic immune deficiency, or developmental changes in utero. Rather than the viral infection dictating disease progression, we explored the possibility that immature neurons might be particularly sensitive to toxins secreted in response to HIV. Primary cultures of rat cortical neurons were exposed to toxic cerebrospinal fluid (CSF) from HIV-infected individuals (CSF(tox)) and evaluated for changes in intracellular calcium and cell death. CSF(tox) had no detectable effect on early neurite outgrowth, calcium regulation, or cell death during the first few days in culture. Starting at Day 4, delayed increases in intracellular calcium appeared in response to CSF(tox). The magnitude of the delayed calcium rise and cell death increased with the age of the culture and correlated with the appearance of synaptophysin immunoreactive varicosities. A similar gradual development of sensitivity was seen during exposure of feline neurons to toxins generated by choroid plexus macrophages after exposure to feline immunodeficiency virus. The possibility that toxin sensitivity is dependent on the presence of synaptic activity is consistent with the rapid pathogenesis in the CNS seen during the first postnatal year. Emerging synaptic activity coupled with other factors such as high metabolic demand in the young nervous system may combine to increase the likelihood of calcium overload and neuronal dysfunction in response to HIV-associated toxins.
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PMID:Development of neuronal sensitivity to toxins in cerebrospinal fluid from HIV-type 1-infected individuals. 1558 98


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