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)

The early transcription region 3 (E3) of group B adenovirus type 35 (Ad35), a serotype isolated primarily from patients with acquired immunodeficiency syndrome and other immunodeficiency disorders, has been partially sequenced. We had previously identified an Ad35 29-kilodalton (kDa) early glycoprotein which, analogous to group C Ad2 E3-19K, associated with major histocompatibility complex class I antigens in the endoplasmic reticulum of infected cells. The open reading frame (ORF) of the Ad35 29-kDa protein has now been identified within a 2-kilobase-pair cloned Ad35 E3 fragment. The predicted amino acid sequence was very similar to that of group B Ad3 E3-19K. In contrast, homology between the Ad35 and Ad2 glycoproteins was limited to five cysteines in identical positions and a 20-amino-acid region proximal to the transmembrane domain. In addition, 20.3- and 20.6-kDa ORFs have been identified downstream from the ORF for the Ad35 glycoprotein. Analogous 20-kDa ORFs are present in the Ad3 E3 region but are not present in Ad2 and Ad5. In contrast, the region analogous to an Ad2 11.6-kDa ORF, which is 9 kDa in size in Ad3, was absent from the expected position within the Ad35 E3 region. Because the E3 region is likely to play an important role in the interaction between virus and host, analysis of the function of the Ad35 E3 proteins should further our understanding of adenovirus pathogenesis.
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PMID:Sequence and genetic organization of adenovirus type 35 early region 3. 317 47

The human immunodeficiency virus type 1-specific Vpu protein is a small integral membrane phosphoprotein that induces degradation of the virus receptor CD4 in the endoplasmic reticulum and, independently, increases the release of progeny virions from infected cells. To address the importance of Vpu for virus replication in primary human cells such as peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM), we used three different sets of monocyte-tropic molecular clones of human immunodeficiency virus type 1: a primary isolate, AD8+, and two chimeric variants of the T-cell-tropic isolate NL4-3 carrying the env determinants of either AD8+ or SF162 monocyte-tropic primary isolates. Isogenic variants of these chimeric viruses were constructed to express either wild-type Vpu or various mutants of Vpu. The effects of these mutations in the vpu gene on virus particle secretion from infected MDM or PBMC were assessed by determination of the release of virion-associated reverse transcriptase into culture supernatants, Western blot (immunoblot) analysis of pelleted virions, and steady-state or pulse-chase metabolic labeling. Wild-type Vpu increased virus release four- to sixfold in MDM and two- to threefold in PBMC, while nonphosphorylated Vpu and a C-terminal truncation mutant of Vpu were partially active on virus release in primary cells. These results demonstrate that Vpu regulates virus release in primary lymphocyte and macrophage cultures in a similar manner and to a similar extent to those previously observed in HeLa cells or CD4+ T-cell lines. Thus, our findings provide evidence that Vpu functions in a variety of human cells, both primary cells and continuous cell lines, and mutations in Vpu affect its biological activity independent of the cell type and virus isolate used.
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PMID:Augmentation of virus secretion by the human immunodeficiency virus type 1 Vpu protein is cell type independent and occurs in cultured human primary macrophages and lymphocytes. 749 79

We investigated a T-cell activation deficiency in a 3-month-old boy with protracted diarrhea, serious cytomegalovirus pneumonia, and a family history (in a brother) of cytomegalovirus infection and toxoplasmosis. In spite of detection of normal number of peripheral lymphocytes, T cells did not proliferate after activation by anti-CD3 and anti-CD2 antibodies, although proliferation induced by antigens was detectable. We sought to determine the origin of this defect as it potentially represented a valuable tool to analyze T-cell physiology. T-cell activation by anti-CD3 antibody or phytohemagglutinin (PHA) led to reduced interleukin-2 (IL-2) production and abnormal nuclear factor-activated T cell (NF-AT; a complex regulating the IL-2 gene transcription) binding activity to a specific oligonucleotide. T-cell proliferation was restored by IL-2. Early events of T-cell activation, such as anti-CD3 antibody-induced cellular protein tyrosine phosphorylation, p59fyn and p56lck kinase activities, and phosphoinositide turnover, were found to be normal. In contrast, anti-CD3 antibody-induced Ca2+ flux was grossly abnormal. Release from endoplasmic reticulum stores was detectable as tested in the presence of anti-CD3 antibody or thapsigargin after cell membrane depolarization in a K+ rich medium, whereas extracellular entry of Ca2+ was defective. The latter abnormality was not secondary to defective K+ channel function, which was found to be normal. A similar defect was found in other hematopoietic cell lineages and in fibroblasts as evaluated by both cytometry and digital video imaging experiments at a single-cell level. This primary T-cell immunodeficiency appears, thus, to be due to defective Ca2+ entry through the plasma membrane. The same abnormality did not alter B-cell proliferation, platelet function, and polymorphonuclear neutrophil (PMN) function. Elucidation of the mechanism underlying this defect would help to understand the physiology of Ca2+ mobilization in T cells.
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PMID:A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. 753 12

The type I membrane protein calnexin functions as a molecular chaperone for secretory glycoproteins in the endoplasmic reticulum with ATP and Ca2+ as two of the cofactors involved in substrate binding. Protease protection experiments with intact canine rough microsomes showed that amino acid residues 1-462 of calnexin are located within the lumen of the endoplasmic reticulum. Expression using the baculovirus Sf9 insect cell system of a recombinant truncated calnexin corresponding to residues 1-462 (calnexin delta TMC) revealed an association in vivo with a coexpressed secretory glycoprotein substrate, human immunodeficiency virus type I gp120. For the in vitro characterization of calnexin delta TMC, we purified this secreted form to homogeneity from the medium of Sf9 cells. We demonstrate that the properties of the purified calnexin delta TMC correspond to those of full-length calnexin in canine microsomes with at least one intramolecular disulfide bond and binding to 45Ca2+. Calnexin delta TMC underwent a marked and reversible conformational change following Ca2+ binding as measured by its resistance to proteinase K digestion of a 60-kDa fragment and also by the change from an oligomeric form of calnexin delta TMC to a monomeric form. We also found that calnexin bound Mg-ATP leading to a conformational change from a monomeric to an oligomeric form that coincided as with markedly increased proteinase sensitivity. Our results identify the luminal domain of calnexin as responsible for binding substrates, Ca2+, and Mg-ATP. Because Ca2+ and ATP are required in vivo for the maintenance of calnexin-substrate interactions, conformational changes in the luminal domain of calnexin induced by Ca2+ and Mg-ATP are relevant to the in vivo function of calnexin as a molecular chaperone.
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PMID:Conformational changes induced in the endoplasmic reticulum luminal domain of calnexin by Mg-ATP and Ca2+. 762 14

Dextrin-2-sulphate (D2S) is a sulphated polysaccharide which inhibits human immunodeficiency virus type 1 infection of T-cells by binding to the cell surface. During our investigations of the nature of this interaction, a cell membrane fraction was prepared by ultracentrifugation from the T-cell line, HPB-ALL. Separation of membrane proteins by sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis and analysis for binding proteins using ligand blotting showed that 3H-D2S bound, in a saturable and displaceable manner, to two regions corresponding to molecular weights of 14,000-18,000 and 28,000-32,000. The N-terminal sequences of two of the major protein components in the 14,000-18,000 region were consistent with those of histones H2B and H3. The presence of histone H2B in the cell membrane preparation was confirmed by immunoblotting and enzyme-linked immunosorbent assay using a specific antibody. Histone standards were used to determine the level of each histone in the cell membrane fraction. In addition, the binding of 3H-D2S to purified histone standards was quantified. These results show that all of the binding of 3H-D2S to proteins in the 14,000-18,000 region of the cell membrane preparation can be attributed to the histones present. In contrast to HPB-ALL cells, a cell membrane fraction from freshly isolated human peripheral blood lymphocytes contained very low levels of histones. However, after culture with phytohaemagglutinin for 3 days the cell membrane fraction contained greatly increased levels of histones. To exclude the possibility of contamination of the cell membrane preparation with histones derived from the nucleus, cell membranes were also prepared using an affinity-based method using polyethyleneimine-cellulose. Immunoblotting of adsorbed plasma membranes showed the presence of histone H2B. SDS-polyacrylamide gels stained for protein also indicated that the preparation contained histones H1, H2A, H3 and H4. In further experiments whole cells were used to avoid contamination from nuclear proteins. Lactoperoxidase mediated 125I labelling, a method specific for radiolabelling cell surface proteins, confirmed the presence of histones H2B, H3 and H4 on the surface of HPB-ALL cells. Also, incubation of HPB-ALL cells or phytohaemagglutinin-activated peripheral blood lymphocytes with D2S caused displacement of histones from the cell surface into the supernatant without altering cell viability. In addition, immunocytochemistry of freshly isolated peripheral blood lymphocytes showed that histone H2B was located predominantly in the nucleus. However, in phytohaemagglutinin-activated peripheral blood lymphocytes immunoreactive material was also prominent in the endoplasmic reticulum and on the plasma membrane.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Extra-nuclear location of histones in activated human peripheral blood lymphocytes and cultured T-cells. 764 32

We have studied the role of intracellular calcium sequestration on human immunodeficiency virus (HIV) production by latently infected T-lymphocytic cells. Inhibition of the sarco-endoplasmic reticulum-type calcium transport ATPases by thapsigargin or cyclopiazonic acid induced activation of HIV production in the CEM-derived ACH-2 cells. An approximately 50% depletion of the thapsigargin-sensitive calcium pools as measured fluorimetrically of Indo-loaded cells fully activated virus production. Viral activation was manifest by increases in soluble viral core p24 production, increases in cellular immunofluorescent staining for viral antigens, and increased viral transcription as measured by HIV long terminal repeat-directed expression of the chloramphenicol acetyltransferase reporter gene. Virus induction could be blocked in a dose-dependent manner by the calcium channel blocker econazole. Virus production by the Jurkat-derived HIV-1-inducible J1.1 cells was not significantly stimulated by thapsigargin. These data indicate that intracellular calcium pool function is involved in the control of the transcription of proviral HIV in a cell type-specific manner within the T-lymphoid lineage and that ACH-2 cells represent a useful model for the study of calcium dependent activation of the transcription of proviral HIV.
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PMID:Stimulation of HIV expression by intracellular calcium pump inhibition. 773 Mar 32

The role of the glycans of the human immunodeficiency virus type 1 transmembrane glycoprotein (gp41) in the intracellular events of Env precursor (gp160) biosynthesis has been examined by the use of a mutant gp160 in which the cluster of conserved glycosylation sites within the gp41 domain (Asn-621, -630 and -642) has been mutated. Expression of the wild-type and mutant forms of gp160 in BHK-21 cells using recombinant vaccinia viruses has shown that the kinetics of the events occurring in the endoplasmic reticulum (ER) were normal: both Env proteins had similar kinetics of disulphide bond formation, as determined by the acquisition of CD4-binding capability, and both had similar kinetics of oligomer formation. However, in contrast to the parental molecule, mutated gp160 displayed relatively slow transport from the cis to the medial Golgi where it was retained in the oligomeric state. Transport to the trans Golgi was impaired, as determined by the sensitivity of gp160 to glycosidases. Cleavage of mutated gp160 at the gp120/gp41 junction was substantially reduced but this was apparently not due to the involvement of the gp41 glycosylation in the cleavage reaction by furin inasmuch as, in the baculovirus system, mutated gp160 could be cleaved when recombinant furin was co-expressed. The reduced cleavage in mammalian cells may thus reflect the impaired routing of mutated Env to the compartment where cleavage occurs. The glycan component of gp41 is, therefore, important for the efficient intracellular transport and processing of gp160. gp160 lacking gp41 carbohydrates is an additional example, among few others, of a protein lacking glycans that is arrested in the Golgi rather than the ER following its biosynthesis.
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PMID:The glycosylation of human immunodeficiency virus type 1 transmembrane glycoprotein (gp41) is important for the efficient intracellular transport of the envelope precursor gp160. 778 80

A replication-defective feline leukemia virus molecular clone, 61B, has been shown to cause immunodeficiency in cats and cytopathicity in T cells after a long latency period when coinfected with a minimally pathogenic helper virus (J. Overbaugh, E. A. Hoover, J. I. Mullins, D. P. W. Burns, L. Rudensey, S. L. Quackenbush, V. Stallard, and P. R. Donahue, Virology 188:558-569, 1992). The long-latency phenotype of 61B has been mapped to four mutations in the extracellular domain of the envelope transmembrane protein, and we report here that these mutations cause a defect in envelope protein processing. Immunoprecipitation analyses demonstrated that the 61B gp85 envelope precursor was produced but that further processing to generate the surface protein (SU/gp70) and the transmembrane protein (TM/p15E) did not occur. The 61B precursor was not expressed on the cell surface and appeared to be retained in the endoplasmic reticulum or Golgi apparatus. Two of the four 61B-specific amino acid changes are located within a putative cysteine loop in a region of TM that is conserved among retroviruses. Introduction of these two amino acid changes into a replication-competent highly cytopathic virus resulted in the production of noninfectious virus that exhibited an envelope-protein-processing defect. This analysis suggests that mutations in a conserved region within a putative cysteine loop affect retroviral envelope protein maturation and viral infectivity.
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PMID:Mutations within a putative cysteine loop of the transmembrane protein of an attenuated immunodeficiency-inducing feline leukemia virus variant inhibit envelope protein processing. 788 59

Expression of the Nef protein encoded by human and simian immunodeficiency viruses results in the specific down-regulation of CD4 from the cell surface in both lymphoid and non-lymphoid cells. In this report, we examine the biosynthesis and cell surface expression of CD4 in the human T cell line, CEM-SS, that has been stably transduced with the SIV nef gene. Quantification of CD4 in Nef-expressing cells reveals that the steady state level of CD4 is significantly reduced as compared to control transductants. The presence of Nef in these cells promotes the degradation of newly synthesized CD4 protein. The biosynthesis and oligosaccharide processing of CD4 in Nef-expressing T cells appears to be normal through the endoplasmic reticulum and Golgi compartments, suggesting that the degradation of CD4 is a late event in the biosynthetic pathway. Treatment with the lysosomotropic agents chloroquine and primaquine prevents the degradation of CD4 in Nef-expressing CEM-SS cells, indicating that the degradation of CD4 likely occurs in an acidic compartment. Thus the reduced cell surface expression observed in Nef-expressing CEM-SS cells is the likely consequence of a Nef-induced sorting of CD4 into a cellular compartment where CD4 is then degraded.
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PMID:The simian immunodeficiency virus Nef protein promotes degradation of CD4 in human T cells. 790 75

The membrane traffic of human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins has been investigated in COS-1 cells transiently expressing the HIV-1 env, vpu, and rev genes. Analysis of oligosaccharide processing revealed that the majority of gp160 remained fully endo-H sensitive throughout a 21-h chase period, and hence cleavage of gp160 to gp120-gp41 took place prior to the creation of hybrid and complex oligosaccharides on gp120. Immunofluorescence microscopy demonstrated that in the absence of CD4 both gp160 and Vpu are targeted to the Golgi apparatus, that can be stained with wheat germ agglutinin or antibodies to the human KDEL receptor. In contrast, gp160 complexed with CD4 was retained in the ER and thus failed to reach the cis-Golgi compartment. Although gp160-bound CD4 has its own half life of 4 h 35 min in the endoplasmic reticulum (ER), co-expression of Vpu accelerated the turnover of CD4 by 5.5-fold and thereby enabled gp160 to be translocated out of the ER to the cis-Golgi compartment. We concluded that Vpu prevents the formation of stable CD4-gp160 complexes in the ER and thus indirectly allows gp160 to accumulate in the Golgi apparatus, where it is selectively retained to produce gp120-gp41.
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PMID:Intracellular membrane traffic of human immunodeficiency virus type 1 envelope glycoproteins: vpu liberates Golgi-targeted gp160 from CD4-dependent retention in the endoplasmic reticulum. 796 87


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