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)

Neurological disorders develop in most people infected with human immunodeficiency virus type 1 (HIV-1). However, the underlying mechanisms remain largely unknown. Here we report that binding of HIV-1 transactivator (Tat) protein to low-density lipoprotein receptor-related protein (LRP) promoted efficient uptake of Tat into neurons. LRP-mediated uptake of Tat was followed by translocation to the neuronal nucleus. Furthermore, the binding of Tat to LRP resulted in substantial inhibition of neuronal binding, uptake and degradation of physiological ligands for LRP, including alpha2-macroglobulin, apolipoprotein E4, amyloid precursor protein and amyloid beta-protein. In a model of macaques infected with a chimeric strain of simian-human immunodeficiency virus, increased staining of amyloid precursor protein was associated with Tat expression in the brains of simian-human immunodeficiency virus-infected macaques with encephalitis. These results indicate that HIV-1 Tat may mediate HIV-1-induced neuropathology through a pathway involving disruption of the metabolic balance of LRP ligands and direct activation of neuronal genes.
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PMID:Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands. 1110 Jan 24

Hallervorden-Spatz syndrome (HSS) is an autosomal recessive neurodegenerative disorder associated with iron accumulation in the brain. Clinical features include extrapyramidal dysfunction, onset in childhood, and a relentlessly progressive course. Histologic study reveals iron deposits in the basal ganglia. In this respect, HSS may serve as a model for complex neurodegenerative diseases, such as Parkinson disease, Alzheimer disease, Huntington disease and human immunodeficiency virus (HIV) encephalopathy, in which pathologic accumulation of iron in the brain is also observed. Thus, understanding the biochemical defect in HSS may provide key insights into the regulation of iron metabolism and its perturbation in this and other neurodegenerative diseases. Here we show that HSS is caused by a defect in a novel pantothenate kinase gene and propose a mechanism for oxidative stress in the pathophysiology of the disease.
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PMID:A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. 1147 80

Leukocytes accumulate at sites of inflammation and immunological reaction in response to locally existing chemotactic mediators. N-formyl peptides, such as fMet-Leu-Phe (fMLF), are some of the first identified and most potent chemoattractants for phagocytic leukocytes. In addition to the bacterial peptide fMLF and the putative endogenously produced formylated peptides, a number of novel peptide agonists have recently been identified that selectively activate the high-affinity fMLF receptor FPR and/or its low-affinity variant FPRL1, both of which belong to the seven-transmembrane (STM), G protein-coupled receptor (GPCR) superfamily. These agonists include peptide domains derived from the envelope proteins of human immunodeficiency virus type 1 (HIV-1) and at least three amyloidogenic polypeptides, the human acute phase protein serum amyloid A, the 42 amino acid form of beta amyloid peptide and a 21 amino acid fragment of human prion. Furthermore, a cleavage fragment of neutrophil granule-derived bactericidal cathelicidin, LL-37, is also a chemotactic agonist for FPRL1. Activation of formyl peptide receptors results in increased cell migration, phagocytosis, release of proinflammatory mediators, and the signaling cascade culminates in heterologous desensitization of other STM receptors including chemokine receptors CCR5 and CXCR4, two coreceptors for HIV-1. Thus, by interacting with a variety of exogenous and host-derived agonists, formyl peptide receptors may play important roles in proinflammatory and immunological diseases and constitute a novel group of pharmacological targets.
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PMID:Receptors for chemotactic formyl peptides as pharmacological targets. 1178 60

The V3 loop of the human immunodeficiency virus (HIV)-1 surface envelope glycoprotein gp120 is a sphingolipid-binding domain mediating the attachment of HIV-1 to plasma membrane microdomains (rafts). Sphingolipid-induced conformational changes in gp120 are required for HIV-1 fusion. Galactosylceramide and sphingomyelin have been detected in highly purified preparations of prion rods, suggesting that the prion protein (PrP) may interact with selected sphingolipids. Moreover, a major conformational transition of the Alzheimer beta-amyloid peptide has been observed upon interaction with sphingolipid-containing membranes. Structure similarity searches with the combinatorial extension method revealed the presence of a V3-like domain in the human prion protein PrP and in the Alzheimer beta-amyloid peptide. In each case, synthetic peptides derived from the predicted V3-like domain were found to interact with monomolecular films of galactosylceramide and sphingomyelin at the air-water interface. The V3-like domain of PrP is a disulfide-linked loop (Cys(179)-Cys(214)) that includes the E200K mutation site associated with familial Creutzfeldt-Jakob disease. This mutation abrogated sphingomyelin recognition. The identification of a common sphingolipid-binding motif in gp120, PrP, and beta-amyloid peptide underscores the role of lipid rafts in the pathogenesis of HIV-1, Alzheimer, and prion diseases and may provide new therapeutic strategies.
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PMID:Identification of a common sphingolipid-binding domain in Alzheimer, prion, and HIV-1 proteins. 1179 5

Axonal damage represented by accumulation of beta-amyloid precursor protein (beta-APP) develops in numerous central nervous system (CNS) diseases including human immunodeficiency virus (HIV) infection. To study the underlying mechanisms of axonal damage associated with HIV CNS infection, the amount of axonal beta-APP immunostaining in the corpus callosum of 24 simian immunodeficiency virus (SIV)-infected macaques and 3 control macaques was measured by computerized image analysis. The amounts of beta-APP accumulation were then compared with time post-inoculation, extent and character of CNS inflammation, and viral load in the CNS measured by the amount of immunohistochemical staining for the viral transmembrane protein gp41. Significant increases over control values were present in 10 of 24 SIV-infected animals. SIV encephalitis was present in 9 of the 10 animals with elevated beta-APP Increases in beta-APP correlated most strongly with levels of SIV gp41 in the brain (p = 0.005), but significant associations with macrophage infiltration and microglial activation (p = 0.04) and infiltration by cytotoxic lymphocytes (p = 0.05) also were identified. These data demonstrate that beta-APP accumulation in the white matter of SIV-infected macaques develops during SIV infection in close correlation with levels of viral replication and may serve as a sensitive marker of neuronal/axonal damage mediated by viral proteins.
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PMID:Accumulation of beta-amyloid precursor protein in axons correlates with CNS expression of SIV gp41. 1182 47

Although Alzheimer's disease (AD) may not involve a transmissible agent, it does involve a pathogenic process similar to that of transmissible prion disorders (both involve a protein that adopts an abnormal pathogenic conformation in which it self-aggregates, forming amyloid deposits in and surrounding neurons) and viral dementias such as human immunodeficiency virus (HIV) encephalitis. The clinical presentation of patients with AD is dominated by cognitive deficits and emotional disturbances that result from dysfunction and degeneration of neurons in the limbic system and cerebral cortex. The pathogenic process in the brain involves deposition of insoluble aggregates of amyloid beta-peptide, oxidative stress and calcium dysregulation in neurons, and activation of inflammatory cytokine cascades involving microglia. However, AD patients also exhibit alterations in immune function. Studies of lymphocytes and lymphoblast cell lines from AD patients and age-matched normal control patients have documented alterations in cytokine and calcium signaling and increased levels of oxidative stress in immune cells from the AD patients. Studies of the pathogenic actions of mutations in presenilins and amyloid precursor protein that cause early-onset familial AD have established central roles for perturbed cellular calcium homeostasis and oxidative stress in the neurodegenerative process. Presenilin and amyloid precursor protein (APP) mutations also increase oxidative stress and perturb calcium signaling in lymphocytes in ways that alter their production of cytokines that are critical for proper immune responses. Immune dysfunction occurs prior to clinical symptoms in mouse models of AD, and brain cytokine responses to immune challenge are altered in presenilin mutant mice, suggesting a causal role for altered immune function in the disease process. Interestingly, immunization of AD mice with amyloid beta-peptide can stimulate the immune system to remove amyloid from the brain and can ameliorate memory deficits, suggesting that it may be possible to prevent AD by bolstering immune function.
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PMID:Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer's disease. 1247 48

Despite the high incidence of cognitive and motor impairment in acquired immunodeficiency syndrome (AIDS) patients, the mechanisms of AIDS-related central nervous system (CNS) pathology are not completely understood. Infection with simian immunodeficiency virus (SIV) in macaques provides an excellent model of AIDS, including human immunodeficiency virus (HIV)-induced CNS pathology and cognitive/behavioral impairment. Co-inoculation with two SIV strains, SIV/17E-Fr and SIV/DeltaB670, accelerates SIV CNS disease, producing SIV encephalitis in over 90% of pig-tailed macaques within 3 months. In the present study, this SIV model was employed to identify cellular and viral correlates of behavioral impairment following SIV infection. Measures of psychomotor speed (simple reaction time), fine motor control (bimanual motor task), and general motor activity (home cage movement) were all adversely affected by SIV disease. Prior to euthanasia, performance was significantly impaired in both a simple reaction time task in 6 of 12 monkeys and a bimanual motor task in 5 of 6 monkeys. All monkeys evaluated (11 of 11) showed significant reductions in spontaneous motor activity. Significant correlations were found between impaired performance on the bimanual motor test and axonal damage (accumulation of beta-amyloid precursor protein in the corpus callosum) as well as increased microglial activation and macrophage infiltration (levels of CD68 and Ham56 immunostaining). These results suggest that axonal damage is related to the behavioral impairment induced by infection with SIV. The axonal damage may result from neuroimmune responses, including microglial and macrophage activation. Therefore, axonal damage may be a morphologic manifestation of neuronal dysfunction that underlies development of behavioral impairment in HIV/SIV CNS infection.
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PMID:Central nervous system correlates of behavioral deficits following simian immunodeficiency virus infection. 1290 90

As a charge pattern recognition molecule, human C1q can bind a range of immunoglobulin and non-immunoglobulin ligands via its carboxy-terminal globular domain and activate the classical complement pathway. Each globular domain has a heterotrimeric organization, composed of the carboxy-terminal halves of one A (ghA), one B (ghB), and one C (ghC) chain. Recently, we have found that the recombinant forms of individual ghA, ghB and ghC bind differentially to IgG, IgM, gp41 peptide 601-613 of human immunodeficiency virus-1 (HIV-1), gp21 peptide 400-429 of human T cell lymphotrophic virus-I (HTLV-I), beta-amyloid peptide, and apoptotic cells, suggesting a modular organization of the globular domain. This paper examines the interaction of ghA, ghB and ghC with two known C1q ligands: Klebsiella pneumoniae porin OmpK36 and salivary agglutinin. In addition, we have used a panel of recombinant single-chain antibodies (scFv) specific for ghA, ghB and ghC in order to map sites on the heterotrimeric globular domain which are likely to interact with IgG1, IgG3, IgM, OmpK36, salivary agglutinin and gp41 loop peptide. The combined use of recombinant ghA, ghB, ghC and single-chain antibodies has revealed at least three ligand-binding sites on the globular domain of C1q: one is IgG- and OmpK36-specific, the second (IgM-binding site) is most likely overlapping with IgG/OmpK36 binding site, and the third (the gp41-binding site) seems to be located at the junction between the collagen and globular domains.
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PMID:Localization of ligand-binding sites on human C1q globular head region using recombinant globular head fragments and single-chain antibodies. 1458 Sep 97

The fluid mosaic model of the plasma membrane has evolved considerably since its original formulation 30 years ago. Membrane lipids do not form a homogeneous phase consisting of glycerophospholipids (GPLs) and cholesterol, but a mosaic of domains with unique biochemical compositions. Among these domains, those containing sphingolipids and cholesterol, referred to as membrane or lipid rafts, have received much attention in the past few years. Lipid rafts have unique physicochemical properties that direct their organisation into liquid-ordered phases floating in a liquid-crystalline ocean of GPLs. These domains are resistant to detergent solubilisation at 4 degrees C and are destabilised by cholesterol- and sphingolipid-depleting agents. Lipid rafts have been morphologically characterised as small membrane patches that are tens of nanometres in diameter. Cellular and/or exogenous proteins that interact with lipid rafts can use them as transport shuttles on the cell surface. Thus, rafts act as molecular sorting machines capable of co-ordinating the spatiotemporal organisation of signal transduction pathways within selected areas ('signalosomes') of the plasma membrane. In addition, rafts serve as a portal of entry for various pathogens and toxins, such as human immunodeficiency virus 1 (HIV-1). In the case of HIV-1, raft microdomains mediate the lateral assemblies and the conformational changes required for fusion of HIV-1 with the host cell. Lipid rafts are also preferential sites of formation for pathological forms of the prion protein (PrPSc) and of the [beta]-amyloid peptide associated with Alzheimer's disease. The possibility of modulating raft homeostasis, using statins and synthetic sphingolipid analogues, offers new approaches for therapeutic interventions in raft-associated diseases.
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PMID:Lipid rafts: structure, function and role in HIV, Alzheimer's and prion diseases. 1498 85

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


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