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: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of the dementia associated with human immunodeficiency virus (HIV) infection is unclear, but has been postulated to be due to indirect effects of HIV infection including the local production of cytokines. To determine which cytokines are produced in the nervous system and to identify any correlations with dementia, cytokine and HIV messenger RNA expression was analyzed by reverse transcriptase-polymerase chain reaction in the brains from 24 HIV-infected patients with and without dementia and 9 HIV-uninfected control subjects. Levels of tumor necrosis factor-alpha messenger RNA were significantly higher and levels of interleukin (IL)-4 messenger RNA were significantly lower in demented compared to nondemented HIV-infected patients. Demented patients also had lower IL-1 beta levels than did nondemented patients. No significant differences were detected in the amounts of leukemia inhibitory factor, IL-6, transforming growth factor-beta 1 and -beta 2, monokine induced by gamma interferon-2 (MIG-2), or interferon-gamma messenger RNAs. IL-10 and IL-2 messenger RNAs were undetectable in all brains examined. Cytokine messenger RNA levels in nondemented HIV-positive patients were similar to those in HIV-negative control subjects. HIV transcripts were more abundant in subcortical white matter than in the basal ganglia, cortex, or deep white matter. Our findings suggest a possible role for tumor necrosis factor-alpha in the development of neurological dysfunction. Increased levels of tumor necrosis factor-alpha messenger RNA were not associated with increased levels of IL-1 beta messenger RNA, suggesting differential regulation of these monokines in acquired immunodeficiency syndrome dementia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. 849 37

Previous studies in patients receiving interferon-alpha (IFN-alpha) therapy and patients with systemic lupus erythematosus have demonstrated that elevated cerebrospinal fluid (CSF) levels of IFN-alpha are associated with cognitive dysfunction. We measured IFN-alpha levels in CSF and blood by ELISA in human immunodeficiency virus (HIV)-positive patients with (n = 21) and without (n = 23) dementia and HIV-negative controls (n = 48). IFN-alpha was significantly elevated in the CSF of HIV-positive patients with dementia compared to those without dementia and controls. An increasing amount of IFN-alpha in the CSF was correlated with the clinical parameter of increasing Memorial Sloan Kettering scores; although these correlations were not statistically significant, they further suggest an association of increased CSF IFN-alpha with neurocognitive dysfunction in AIDS. Immunocytochemical staining of brains demonstrated IFN-alpha-positive macrophages and astrocytes in frontal cortex and white matter and IFN-alpha mRNA was detected by reverse transcriptase-polymerase chain reaction, further indicating that IFN-alpha is made by cells within the brain and suggesting that the significant increases of IFN-alpha protein found in the CSF of patients with HIV-associated dementia complex are derived from intrinsic brain cells such as macrophages and astrocytes. Increased local production of IFN-alpha during HIV infection may contribute directly or indirectly to the pathogenesis of HIV-associated dementia.
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PMID:A potential role for interferon-alpha in the pathogenesis of HIV-associated dementia. 890 53

A majority of human immunodeficiency virus type I (HIV-1)-infected-individuals manifest a plethora of central nervous system (CNS) diseases unrelated to opportunistic infections, including acquired immune deficiency syndrome (AIDS)-dementia complex (ADC), encephalitis, and various other disorders of the CNS. A series of devastating clinical conditions in the CNS of certain HIV-1-infected-individuals may be caused by infection of cells in the brain parenchyma. ADC is characterized by cognitive dysfunction, motor difficulties, coordination abnormalities and other neurological signs and symptoms, which develop in many HIV-1-infected-individuals. The precise molecular mechanisms leading to AIDS dementia remain incompletely explained. Various mechanisms including cytokine dysregulation, toxic effects of viral proteins and release of certain toxic substances from macrophages, especially nitric oxide, have been implicated as pathogenic mediators in the development of ADC. We have examined post mortem CNS tissues collected from 22 patients, previously diagnosed with AIDS, to explore if nitric oxide is responsible for the observed pathology in ADC. As controls, we utilized tissues collected from the brains of patients who expired without AIDS or other CNS pathologies. In addition, we also utilized post-mortem brain tissues from eight patients who were diagnosed with multiple sclerosis (MS) and were found to express inducible nitric oxide synthase (iNOS) in our previous studies, as positive controls. Highly sensitive in situ reverse transcriptase-initiated polymerase chain reaction (RT-IS-PCR) studies demonstrated that iNOS mRNA was present in the CNS tissues from all the positive MS controls, but were absent in all 22 specimens from AIDS patients, as well as in the brain tissues from normal controls. We have also analyzed the tissues for the presence of the NO reaction product, nitrotyrosine, to evaluate the presence of a protein nitrosalation adduct. Nitrotyrosine was not demonstrable in any of the AIDS brains. These findings indicate that iNOS may not play a significant role in the neuropathogenesis of most cases of ADC.
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PMID:Absence of the inducible form of nitric oxide synthase in the brains of patients with the acquired immunodeficiency syndrome. 911 Nov 78

Entry of the type 1 human immunodeficiency virus into most cells requires the presence of the CD4 protein in combination with one of several recently described co-receptors. CXCR-4 (fusin) was the first identified, and it serves as co-receptor for T-cell-line tropic (T-tropic) HIV-1 isolates. To determine the expression of CXCR-4 in the brain, a major target of HIV pathology, we used immunohistochemistry and reverse transcriptase polymerase chain reaction with CXCR-4-specific antibodies and probes. We found that CXCR-4 was expressed in several cell types in brain, but notably in neurons and microglia, a finding that was replicated in tissue culture. The study of the expression of CXCR-4 in the brain, which may be one of many chemokine receptors in the central nervous system, may provide further insight into the interactions between brain cells, pathogens, and the immune system, and help understand the pathogenesis of HIV dementia.
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PMID:CXCR-4 (Fusin), a co-receptor for the type 1 human immunodeficiency virus (HIV-1), is expressed in the human brain in a variety of cell types, including microglia and neurons. 932 37

To determine whether cerebrospinal fluid (CSF) viral burden measurements can assist in the evaluation of human immunodeficiency virus (HIV)-associated neurocognitive disorders, we quantified HIV type 1 (HIV-1) RNA in CSF. Because previous findings suggested that disease stage, lymphocytic pleocytosis, and HIV-1 RNA levels in plasma may influence CSF viral burden, these variables were examined as potential modifying factors. HIV-1 RNA levels were quantified by using a reverse transcriptase-polymerase chain reaction assay. Performance on a comprehensive neuropsychological (NP) battery was noted in 97 prospectively enrolled, HIV-infected subjects. Among subjects with acquired immunodeficiency syndrome (AIDS) (<200 CD4+ lymphocytes), NP impairment was associated with significantly higher CSF RNA levels (3.1 vs 1.8 log10 copies/ml; p = 0.02); most impaired subjects met criteria for HIV-associated dementia or minor cognitive-motor disorder. In subjects without AIDS, CSF RNA and NP impairment were unrelated. Before AIDS, CSF RNA was strongly correlated to plasma RNA and to pleocytosis, but in AIDS, CSF and plasma RNA were independent. In conclusion, we found elevated CSF HIV-1 RNA levels in NP impaired subjects with AIDS. Before AIDS, systemic viral replication, possibly through CD4+ mononuclear cell trafficking, may govern virus levels in CSF, whereas in AIDS, CD4 cell depletion may unmask a correlation between increased productive central nervous system HIV infection and clinical neurocognitive disorders.
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PMID:Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. HIV Neurobehavioral Research Center Group. 966 9

We have isolated a novel Alu sequence-containing cDNA, designated AD7c-NTP, that is expressed in neurons, and overexpressed in brains with Alzheimer's disease (AD). The 1,442-nucleotide AD7c-NTP cDNA encodes an approximately 41-kD protein. Expression of AD7c-NTP was confirmed by nucleic acid sequencing of reverse transcriptase PCR products isolated from brain. AD7c-NTP cDNA probes hybridized with 1. 4 kB mRNA transcripts by Northern blot analysis, and monoclonal antibodies generated with the recombinant protein were immunoreactive with approximately 41-45-kD and approximately 18-21-kD molecules by Western blot analysis. In situ hybridization and immunostaining studies localized AD7c-NTP gene expression in neurons. Using a quantitative enzyme-linked sandwich immunoassay (Ghanbari, K., I. Beheshti, and H. Ghanbari, manuscript submitted for publication) constructed with antibodies to the recombinant protein, AD7c-NTP levels were measured under code in 323 clinical and postmortem cerebrospinal fluid (CSF) samples from AD, age-matched control, Parkinson's disease, and neurological disease control patients. The molecular mass of the AD7c-NTP detected in CSF was approximately 41 kD. In postmortem CSF, the mean concentration of AD7c-NTP in cases of definite AD (9.2+/-8.2 ng/ml) was higher than in the aged control group (1.6+/-0.9; P < 0.0001). In CSF samples from individuals with early possible or probable AD, the mean concentration of AD7c-NTP (4.6+/-3.4) was also elevated relative to the levels in CSF from age-matched (1.2+/-0.7) and neurological disease (1.0+/-0.9) controls, and ambulatory patients with Parkinson's disease (1.8+/-1.1) (all P < 0.001). CSF levels of AD7c-NTP were correlated with Blessed dementia scale scores (r = 0. 66; P = 0.0001) rather than age (r = -0.06; P > 0.1). In vitro studies demonstrated that overexpression of AD7c-NTP in transfected neuronal cells promotes neuritic sprouting and cell death, the two principal neuroanatomical lesions correlated with dementia in AD. The results suggest that abnormal AD7c-NTP expression is associated with AD neurodegeneration, and during the early stages of disease, CSF levels correlate with the severity of dementia.
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PMID:Characterization of the AD7C-NTP cDNA expression in Alzheimer's disease and measurement of a 41-kD protein in cerebrospinal fluid. 939 56

Blood-brain barrier dysfunction has been postulated to be important in the pathogenesis of HIV dementia. This study used an in vitro model of the blood-brain barrier to determine the effects of ovine lentivirus (OvLV) infection on endothelial cells. The replication of two American OvLV isolates and two lcelandic OvLV isolates in pure cultures of endothelial cells isolated from brain was compared to replication in endothelial cells from adipose, lung, and aorta. Inoculation with the two American isolates resulted in 100 times greater reverse transcriptase (RT) activity in supernatant of the microvascular endothelial cells (brain, lung, and adipose) than in the macrovascular endothelial cells (aorta). Conversely, inoculation with the two lcelandic isolates resulted in 100 times higher RT activity in aortic, lung, and adipose endothelial cells than in the brain endothelial cells. Transmission electron microscopy of the brain capillary endothelial cells infected with the American isolates revealed polarized viral budding from the lateral cell membrane and a loss of tight junctions. Replication of OvLV in brain capillary endothelial cells could play a role in the pathogenesis of lentiviral encephalitis by altering blood-brain barrier integrity.
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PMID:Differential replication of ovine lentivirus in endothelial cells cultured from different tissues. 940 Jun 4

HIV-1 infection results in a dementing illness affecting 20% of patients with AIDS. Several HIV-1 genes have been implicated in the pathogenesis of HIV-induced neurological disease. To search for distinct HIV-1 sequences associated with the development of dementia, brain-derived tat, env, and pol sequences were examined from AIDS patients defined pre-mortem as demented (HIV-D)[n=5] or non-demented (HIV-ND)[n=5]. Estimations of evolutionary distances and frequency of non-synonymous mutation rates revealed significant differences between brain-derived tat, env, and pol-encoded reverse transcriptase sequences. However, established zidovudine-associated resistance mutations in reverse transcriptase sequences were identified in only one HIV-D and one HIV-ND patient despite prolonged treatment of some patients. Non-synonymous/synonymous substitution rates among the tat sequences derived from patients with HIV-D were significantly higher compared to the HIV-ND group (P < 0.001). The ratios of transversions to transitions were also significantly higher among the HIV-D tat sequences (P< 0.01). Phylogenetic analyses showed clustering of sequences from each clinical group among the brain-derived tat and env sequences. These studies indicated that differing selective forces act on individual HIV-1 genes in the brain which may influence the development of dementia.
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PMID:Brain-derived HIV-1 tat sequences from AIDS patients with dementia show increased molecular heterogeneity. 971 30

About one third of patients with HIV infection show neurological complications with considerable morbidity and high mortality. This is an actualized review of the most important neurological manifestations resulting from primary HIV infection, from secondary opportunistic infections, or as complications of antiretroviral therapy. The primary neurological manifestations, including HIV-associated dementia complex, myelopathies, peripheral neuropathies and myopathies, the more common opportunistic infections, primary central nervous system lymphoma and cerebrovascular diseases, are discussed in the light of new evidence in diagnosis, therapy and prognosis. Cognitive and psychiatric symptoms, visual changes, headache, seizures, dizziness, involuntary movements, gait disturbances, cranial neuropathies and focal deficits are the common neurological symptoms in HIV infection which are described under the aspect of differential diagnosis. It is important to bear in mind that nearly all information available to date on this subject concerns HIV patients in the period before combination therapies (including protease inhibitors). The introduction of highly active antiretroviral therapy (HAART) with protease inhibitors in 1995, and non-nucleoside reverse transcriptase inhibitors, have opened up new therapeutic modalities with a new emphasis on earlier detection and treatment of neurological complications. The prognosis of different HIV-associated neurological diseases has considerably improved, as recently shown in the case, for example, of progressive multifocal leucoencephalopathy.
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PMID:[Neurological complications of HIV infection. Review: new diagnostic, therapeutic and prognostic aspects]. 1081 41

We report a 63-year-old male with HIV encephalopathy, whose initial symptom was acutely progressing dementia. He tested positive for HIV antibody, and HIV-RNA count was 2.8 x 10(5) copy/ml. All opportunistic infections that could cause dementia were ruled out. Dementia remarkably improved after the combination antiretroviral therapy of three types of drugs, two being nucleoside analog reverse transcriptase inhibitors and one being a protease inhibitor. The combination therapy could be very effective for the treatment of HIV dementia.
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PMID:[A case of HIV encephalopathy with dementia which showed significant improvement after the combination antiretroviral therapy]. 1083 42


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