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)

A 24 year old male with a history of eczema, recurrent mild infections, and thrombocytopenia consistent with the Wiskott-Aldrich syndrome (WAS) presented with a mediastinal mass, generalized lymphadenopathy, splenomegaly, and severe thrombocytopenia. Studies of immune function including immunoglobulin levels and T-cell subsets were normal. Furthermore, his T lymphocytes proliferated normally in response to phytohemagglutinin, concanavalin A, and the combination of neuraminidase/galactose oxidase. However, their proliferative responses to anti-CD43 antibody and periodate were diminished, consistent with the clinical diagnosis of WAS. An initial inguinal lymph node biopsy surprisingly revealed Kaposi sarcoma. However, following splenectomy to increase the platelet count, biopsy of the mediastinal mass revealed T-cell large cell lymphoma. Studies of biopsied tissue for the presence of Epstein-Barr virus and cytomegalovirus were negative, as were studies of blood, including the polymerase chain reaction, for the presence of the human immunodeficiency virus (HIV). This is the first report of Kaposi sarcoma arising in a patient with a congenital immunodeficiency syndrome. Although Kaposi sarcoma can arise in the face of the severe immunosuppression that follows allograft transplantation and in patients infected with HIV, we postulate that longevity in the face of mild immunosuppression was the major factor in the development of Kaposi sarcoma in this patient.
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PMID:Coincident Kaposi sarcoma and T-cell lymphoma in a patient with the Wiskott-Aldrich syndrome. 131 18

The role of carbohydrates in the immunogenicity of human immunodeficiency virus type 1 (HIV-1) glycoproteins (gp160 and gp120) remains poorly understood. We have analyzed the specificity and neutralizing capacity of antibodies raised against native gp160 or against gp160 deglycosylated by either endo F-N glycanase, neuraminidase, or alpha-mannosidase. Rabbits immunized with these immunogens produced antibodies that recognized recombinant gp160 (rgp160) from HIV-1 in a radioimmunoassay and in an enzyme-linked immunosorbent assay. Antibodies elicited by the different forms of deglycosylated gp160 were analyzed for their reactivity against a panel of synthetic peptides. Compared with anti-native gp160 antisera, serum reactivity to most peptides remained unchanged, or it could increase (peptide P41) or decrease. Only antibodies raised against mannosidase-treated gp160 failed to react with a synthetic peptide (peptide P29) within the V3 loop of gp120. Rabbits immunized with desialylated rgp160 generated antibodies which recognized not only rgp160 from HIV-1 but also rgp140 from HIV-2 at high titers. Although all antisera produced against glycosylated or deglycosylated rgp160 could prevent HIV-1 binding to CD4-positive cells in vitro, only antibodies raised against native or desialylated gp160 neutralized HIV-1 infectivity and inhibited syncytium formation between HIV-1-infected cells and noninfected CD4-positive cells, whereas antibodies raised against alpha-mannosidase-treated gp160 inhibited neither virus replication nor syncytium formation. These findings indicate that the carbohydrate moieties of gp160 can modulate the specificity and the protective efficiency of the antibody response to the molecule.
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PMID:Influence of carbohydrate moieties on the immunogenicity of human immunodeficiency virus type 1 recombinant gp160. 134 97

The human immunodeficiency virus-1 (HIV-1) Tat protein has previously been shown to transactivate the HIV-1-LTR when added exogenously to HeLa, H9 lymphocytic and U937 promonocytic cells growing in culture. Here we show that Tat enters these cells by adsorptive endocytosis. Tat appears to bind non-specifically to the cell surface, with greater than 10(7) sites per cell. A specific receptor was not detected by protein crosslinking experiments, and uptake was not affected by treating cells with trypsin, heparinase or neuraminidase. Uptake and transactivation could be inhibited by incubation with heparin, dextran sulfate, an anti-Tat monoclonal antibody, or by incubation at 4 degrees C. In contrast, transactivation by Tat was markedly stimulated by the addition of basic peptides, such as Tat 38-58 or protamine. Fluorescence experiments with rhodamine-conjugated Tat show punctate staining on the cell surface and then localization to the cytoplasm and nucleus. The lack of a specific receptor makes it unclear whether Tat uptake is biologically important in HIV infection, however, the efficiency of uptake raises the possibility that Tat may be useful for delivery of protein molecules into cells.
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PMID:Endocytosis and targeting of exogenous HIV-1 Tat protein. 205 Jan 10

The three-dimensional structure of human rhinovirus 14 has a deep surface depression or "canyon" encircling each of the twelve fivefold vertices. The canyon's surface is inaccessible to the broad antigen binding region of antibodies, permitting conservation of residues that might be required for host cell receptor recognition without danger of attack by the host's immune system. In contrast, the exposed surface features, where neutralizing antibodies are known to bind, change rapidly under pressure from the host's immune system. It was, therefore, hypothesized that this depression was the site of receptor attachment. Similar, but smaller, depressions had been observed previously on both the hemagglutinin and neuraminidase spikes of influenza virus. These have also been shown to be the site of host cell interaction. Although support for the canyon hypothesis was only circumstantial in the first place, there are now extensive confirmatory data. These include site-specific mutations of residues in the canyon and conformational changes induced in the canyon by the binding of small organic molecules, all of which alter receptor attachment. The strategy used in human rhinovirus 14 to protect the viral receptor attachment site from immune surveillance may be utilized not only in other picornaviruses but also in many other types of viruses including human immunodeficiency virus.
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PMID:The canyon hypothesis. 256 Sep 13

The three-dimensional structure of human rhinovirus 14 has a deep surface depression or "canyon" encircling each of the twelve 5-fold vertices. The canyon's surface is inaccessible to the broad antigen binding region of antibodies, permitting conservation of residues that might be required for host cell receptor recognition without danger of attack by the host's immune system. In contrast, the exposed surface features, where neutralizing antibodies are known to bind, change rapidly under pressure from the host's immune system. It was, therefore, hypothesized that this depression was the site of receptor attachment. Similar, but smaller, depressions had been observed previously on both the hemagglutinin and neuraminidase spikes of influenza virus. These have also been shown to be the site of host cell interaction. Although support for the canyon hypothesis was only circumstantial in the first place, there are now extensive confirmatory data. These include site-specific mutations of residues in the canyon and conformational changes induced in the canyon by the binding of small organic molecules, all of which alter receptor attachment. The strategy used in human rhinovirus 14 to protect the viral receptor attachment site from immune surveillance may be utilized not only in other picornaviruses but also in many other types of viruses including human immunodeficiency virus.
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PMID:The canyon hypothesis. Hiding the host cell receptor attachment site on a viral surface from immune surveillance. 267 Sep 20

The Wiskott-Aldrich syndrome (WAS) is an X-linked immune deficiency disorder characterized clinically by both lymphocyte and platelet dysfunction. Studies of WAS T lymphocytes have revealed deficient or defective cell surface expression of the highly O-glycosylated leucocyte sialoglycoprotein CD43. To further elucidate the basis for, and functional relevance of, CD43 modifications on WAS lymphocytes, we have studied lymphocytes from two WAS patients with regard to membrane glycoprotein profile and mitogen-induced proliferative responses. CD43 was found to be either absent or altered in size on peripheral blood lymphocytes and lectin-stimulated T cells from both patients. Compared with control cells, the WAS lymphocytes displayed reduced, but measurable proliferative responses to lectins and neuraminidase/galactose oxidase, and virtually no response to periodate, a mitogenic agent which targets sialic acid residues on membrane glycoproteins such as CD43. Analysis of activities of three glycosyltransferases involved in O-glycosylation revealed marked reduction in the level of activity of UDP-N-acetylglucosamine: Gal beta 1-3GalNAc-R beta-1,6-N-acetylglucosamine (beta-1,6-GlcNAc) transferase in one WAS patient and no detectable activity of this enzyme in a second. beta-1,6-GlcNAc transferase activity has recently been shown to increase during T cell activation coincident with changes in the O-linked glycans on CD43. A selective reduction of this glycosyltransferase in WAS lymphocytes suggests that O-linked oligosaccharides may be important to the structure of membrane glycoproteins involved in lymphocyte activation.
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PMID:Altered expression of leucocyte sialoglycoprotein in Wiskott-Aldrich syndrome is associated with a specific defect in O-glycosylation. 280 29

Swine influenza A (H1N1) viruses were isolated from two people in Switzerland and one in the Netherlands in early 1986. In haemagglutination-inhibition and neuraminidase-inhibition assays, the three viruses were closely related to one another and to the A/New Jersey/8/76 strain. The Swiss patients showed only mild symptoms, whereas the Dutch patient suffered from severe pneumonia. Two of the patients had been in close contact with diseased pigs. No such contact could be established for the third patient. None of the three individuals was known to suffer from immunodeficiency. No man-to-man transmission of the virus has been detected.
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PMID:Isolation of swine-like influenza A(H1N1) viruses from man in Switzerland and The Netherlands. 321 96

The role of the cytoplasmic tail and transmembrane anchor of the human parainfluenza virus type 3 (HPIV3) hemagglutinin-neuraminidase (HN) glycoprotein in promoting cell fusion was investigated. A series of amino terminal deletion mutants (d10, d20, d27, d31, d40, d44, and d73) were compared for processing, cell surface expression, and maintenance of their biological attributes by recombinant expression of mutant genes using a plasmid vector (pcDL-SR alpha-296) in CV-1 and HeLa cells. To determine the fusion promoting activity (FPA) of the various mutant proteins, a simple assay was developed which quantified the fusion of two different HeLa cell types. One of the cell types, HeLa-tat, constitutively expressed the human immunodeficiency virus type I (HIV-1) tat protein from a Moloney murine leukemia virus long terminal repeat (LTR), while the second cell type, HeLa beta-gal, contained a reporter gene, beta-galactosidase, under the control of an HIV1-LTR. Fusion of mixed HeLa cell monolayers (50:50, HeLa-tat: HeLa beta-gal), following transfection with appropriate plasmids, resulted in transactivation of the reporter gene which was then measured by direct staining of cells or using cell lysates with appropriate substrates. Cell fusion was observed only when both the HPIV3 F and functional HN proteins were both co-transfected into cells. Of the seven deletion mutants examined, only d10, d20, d27 and d31 were expressed to significant levels on the cell surface and only these four mutant proteins maintained FPA. Compared with the wt HN at 48 h post transfection, d10 and d20 had enhanced FPA (119% and 158%, respectively), while d27 and d31 were diminished (74% and > 4%, respectively). Analysis of protein expression suggested that the reason for the increase in FPA of the mutant proteins was that the levels of protein expressed at the cell surface was twofold or threefold higher for d10 and d20, respectively, compared to the wt HN.
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PMID:Human parainfluenza virus type 3: analysis of the cytoplasmic tail and transmembrane anchor of the hemagglutinin-neuraminidase protein in promoting cell fusion. 765 94

The human immunodeficiency virus type 2 (HIV-2) strain LAV-2/B is able to infect a variety of human cell lines via a CD4-independent pathway. We have used the glycosylation inhibitors tunicamycin, swainsonine, and deoxymannojirimycin to further characterize this putative alternative receptor for HIV-2 (LAV-2/B). These antibiotics resulted in an increase (5- to 30-fold) in the susceptibility of a variety of CD4- human cell lines to infection by LAV-2/B (RD, HeLa, HT29, Rsb, Heb7a, Hos, and Daudi). Several nonprimate cell lines (mink Mv-1-lu, rabbit SIRC, hamster a23, mouse NIH 3T3, cat CCC, and rat HSN) remained resistant to infection by LAV-2/B after treatment with glycosylation inhibitors, suggesting that they do not express the HIV-2 CD4-independent receptor. Two of these nonprimate cell lines are readily infected by HIV-2 when they express CD4 (Mv-1-lu and CCC). Treatment of human cells with neuraminidase had no effect on subsequent infection by LAV-2/B, suggesting that the increase in susceptibility to infection of deglycosylated cells is not due to a change in the electrostatic charge of the cell surface. Treatment of RD CD4- cells and HeLa CD4+ cells with a variety of proteases resulted in a 75 to 90% decrease in infection by LAV-2/B when compared with untreated cells. Taken together, all these data suggest that HIV-2 can utilize a membrane glycoprotein other than CD4 to attach and fuse with a variety of human cells.
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PMID:Reduced glycosylation of human cell lines increases susceptibility to CD4-independent infection by human immunodeficiency virus type 2 (LAV-2/B). 774 86

The fusogenic activities of enveloped-virus glycoproteins were analyzed by using a quantitative, sensitive, rapid, and highly versatile recombinant vaccinia virus-based assay measuring activation of a reporter gene upon fusion of two distinct cell populations. One population uniformly expressed vaccinia virus-encoded viral glycoproteins mediating specific binding and fusion activities; the other expressed the corresponding cellular receptor(s). The cytoplasm of one population also contained vaccinia virus-encoded bacteriophage T7 RNA polymerase; the cytoplasm of the other contained a transfected plasmid with the Escherichia coli lacZ gene linked to the T7 promoter. When the two populations were mixed, cell fusion resulted in activation of the LacZ gene in the cytoplasm of the fused cells; beta-galactosidase activity was assessed by colorimetric assay of detergent cell lysates or by in situ staining. We applied this approach to study the human immunodeficiency virus type 1 envelope glycoprotein (Env)-CD4 interaction. Beta-Galactosidase was detected within 1 h after cell mixing and accumulated over the next several hours. Cell fusion dependence was demonstrated by the strict requirement for both CD4 and functional Env expression and by the inhibitory effects of known fusion-blocking monoclonal antibodies and pharmacological agents. Quantitative measurements indicated much higher sensitivity compared with analysis of syncytium formation. The assay was used to probe mechanisms of the cell type specificity for Env-CD4-mediated fusion. In agreement with known restrictions, cell fusion occurred only when CD4 was expressed on a human cell type. Membrane vesicle transfer experiments indicated that CD4 initially produced in either human or nonhuman cells was functional when delivered to human cells, suggesting that the fusion deficiency with nonhuman cells was not associated with irreversible defects in CD4. We also demonstrated that the infectivity specificities of different human immunodeficiency virus type 1 isolates for peripheral blood lymphocytes versus continuous CD4+ cell lines were associated with corresponding fusion selectivities of the respective recombinant Env proteins. The assay enabled analysis of the fusogenic activity of the fusion glycoprotein/hemagglutinin-neuraminidase of the paramyxovirus simian virus 5. This system provides a powerful tool to study fusion mechanisms mediated by enveloped-virus glycoproteins, as well as to screen fusion-blocking antibodies and pharmacological agents.
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PMID:Fusogenic mechanisms of enveloped-virus glycoproteins analyzed by a novel recombinant vaccinia virus-based assay quantitating cell fusion-dependent reporter gene activation. 805 23


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