Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human spuma retrovirus or foamy virus integrase (HFV IN) is an enzymatically active protein consisting of domains similar to other retroviral integrases: an amino-terminal HH-CC finger, a centrally located region with the conserved D, D-35-E protein motif required for catalytic activity and oligomerization, and at least one DNA binding domain implicated in the 3' DNA processing activity and integrase. Recombinant, purified HFV IN protein carrying 10 histidine residues displays a site-specific endonuclease, an integrase, and a disintegrase activity with oligonucleotide substrates that mimic the viral long terminal repeat (LTR) ends. Site-directed mutagenesis of conserved HFV IN residues of the catalytic domain had increased endonuclease and disintegrase activities. Deletion mutants at both ends of the HFV IN protein were generated, purified, and characterized. Unexpectedly, it was found that the HFV integrase and disintegrase activities require an intact NH2-terminal sequence and that COOH-terminal deletions led to an increase in disintegrase activity. The HH-CC finger of HFV IN was exchanged with that of the human immunodeficiency virus-1 (HIV-1) IN protein. The resulting chimeric IN had a 3' processing activity that utilized the HFV LTR instead of the HIV LTR, indicating that the central domain is crucial for substrate recognition. Functional complementation of the amino-terminal deletion mutant of HFV IN was achieved by a carboxyl-terminal deletion mutant of the chimeric IN, resulting in high levels of integrase activity.
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PMID:Characterization of the human spuma retrovirus integrase by site-directed mutagenesis, by complementation analysis, and by swapping the zinc finger domain of HIV-1. 785 75

A 12 year old boy was found to be deficient in immunoglobulins (Ig) A, G2 and G4, and common variable immunodeficiency was diagnosed. He also had cyclic thrombocytopenia at intervals of approximately 28-30 days. His bone marrow revealed normocellular with slightly decreased megakaryocytes. In vitro colony assays showed markedly imparied megakaryocytopoiesis, erythropoiesis and granulopoiesis. Platelet-associated IgG was elevated at his thrombocytopenic phase. Direct Coombs' test was repeatedly positive. Although not defined at present, we suggest the autoimmune nature of the disease.
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PMID:A case of common variable immunodeficiency associated with cyclic thrombocytopenia. 787 84

This is a case report and family study of a 65-year-old man with chronic prurigo lesions, in whom we demonstrated a selective deficiency of circulating T-helper/inducer lymphocytes (CD4+), in the absence of any apparent predisposing disease. He is seronegative for human immunodeficiency virus (HIV types 1 and 2) and human T-cell lymphotropic virus (HTLV-I and HTLV-II), and fulfils the criteria for the syndrome of idiopathic CD4+ T lymphocytopenia. He has an atopic diathesis, has had a severe adult chickenpox infection, chronic staphylococcal infections, tinea pedis and recalcitrant warts. He has also suffered from respiratory infections, for which no specific aetiological agent has been identified. His peripheral total lymphocyte count has been persistently abnormal since it was first measured in 1969. He has a marked CD4+ T-cell lymphocytopenia. His son, who does not have any skin disorder, has a low CD4+ T-cell count.
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PMID:Idiopathic CD4+ lymphocytopenia associated with chronic pruritic papules. 791 13

The nucleocapsid protein NCp7 of human immunodeficiency virus type 1 (HIV-1), which has key functions in the virus life cycle, possesses two zinc fingers of the CX2CX4HX4C type characterized by three successive loops containing a tetrahedrally coordinated zinc atom. The replacement of any cysteine by a serine in either finger has been shown to result in the production of noninfectious viruses, probably by impairing the biological functions of NCp7. In order to more precisely elucidate the structural role of the zinc finger motif, His23 was replaced by Cys in the proximal finger of the peptide (13-64)NCp7 which retains NCp7 activities in vitro. The peptide Cys23(13-64)NCp7 was synthesized by solid phase and studied by 2D 1H NMR and molecular modeling. The His to Cys modification causes important structural modifications of the N-terminal zinc finger which impair the spatial proximity of the two zinc fingers as shown by the disappearance of several interresidue NOEs. The side chains of Val13, Lys14, Phe16, Thr24, Ala25, Trp37, Gln45, and Met46, which are thought to be involved in nucleic acid recognition, are no longer found clustered in the Cys23(13-64)NCp7 mutant as they are in the wild-type NCp7 structure. In vitro, Cys23(13-64)NCp7 is unable to tightly interact with the viral RNA or replication primer tRNA(Lys,3). The Cys23(NCp7) mutation was introduced into an infectious HIV-1 molecular clone, and virions produced upon DNA transfection into cells were analyzed for their viral protein and RNA compositions as well as for their infectivity. Results show that, while the Cys23(NCp7) mutation does not impair virion production, viruses contain a low amount of degraded viral RNA and are not infectious. These findings suggest that a bona fide conformation of the HIV-1 NCp7 is critical for the packaging of viral RNA, its stability in virions, and virus infectivity.
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PMID:1H NMR structure and biological studies of the His23-->Cys mutant nucleocapsid protein of HIV-1 indicate that the conformation of the first zinc finger is critical for virus infectivity. 791 87

We describe a 39 years-old male hemophilia A patient with acquired immunodeficiency syndrome (AIDS) developing to disseminated intravascular coagulation (DIC) due to gastric carcinoma. He had been diagnosed as human immunodeficiency virus (HIV) sero-positive in 1990. Since then, he has been treated by the oral administration of zidovudine (AZT), dideoxyinosine (ddI) and intravenous administration of glycyrrhizin. In September 1990, he suddenly complained abdominal pain with bloody stool. His condition deteriorated in spite of our intensive treatment for DIC. He died of multiple organ failure (MOF) due to DIC. The autopsy findings showed gastric carcinoma, defined of signet ring cell carcinoma histopathologically. But neither opportunistic infection nor other cause of DIC were observed.
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PMID:[An autopsy case of AIDS with hemophilia A who died of DIC and gastrointestinal bleeding associated with gastric carcinoma (signet ring cell carcinoma)]. 796 58

We describe the case of a human immunodeficiency virus-infected 34-year-old man with progressive multifocal leukoencephalopathy (PML). His case displayed unusual features, including a bizarre movement disorder, predominant involvement of the subcortical U fibers on neuropathologic examination, and the absence of MRI abnormalities suggestive of PML. Anatomic-clinical correlations are discussed.
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PMID:Isolated motor control dysfunction related to progressive multifocal leukoencephalopathy during AIDS with normal MRI. 799 Nov 25

The protease encoded by the human immunodeficiency virus-1 (HIV-1) is essential for the processing of viral polyproteins into mature viral proteins. The 99-residue protease from HIV-1 contains two generally conserved cysteine residues, one of which (Cys-67) is located on the solvent-exposed surface. It was shown previously that Cys-67 of the native enzyme reacted with 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB, Ellman's reagent) at pH 6.2, causing a reversible inactivation of the protease. However, there was no reaction when the protein was denatured in 6 M guanidine hydrochloride, implying that the native conformation rendered Cys-67 more reactive. To investigate the structural basis of the lowered pKa in the native protein, we synthesized a 17-residue peptide matching the sequence of residues 59-75. The reactivity of this synthetic peptide with DTNB mimicked that of the protease, being more reactive in the absence of 6 M guanidine hydrochloride than in its presence. It was possible that His-69 or Lys-70 could facilitate ionization of the SH group of Cys-67, which is required for reaction with DTNB. Apparently both residues are important, because increased reactivity of the native peptide was eliminated when either His-69 or Lys-70 were changed to Ala. Replacement of His-69 by Glu reversed the reactivity, so that the native peptide was less reactive than that denatured in guanidine hydrochloride. Thus, the reactivity of Cys-67 is modulated by the charges on residues 69 and 70 in the protein. The presence of His-69 and Lys-70 renders the native protease especially susceptible to oxidation and disulfide formation. The resulting reversible inactivation of the protease may be important in the normal regulation of the viral life cycle, a suggestion supported by the strong conservation of the residues in this region.
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PMID:Reactivity of cysteine-67 of the human immunodeficiency virus-1 protease: studies on a peptide spanning residues 59 to 75. 805 89

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency characterized by eczema, thrombocytopenia, and recurrent infections. Linkage studies have placed the gene at Xp11.22-p11.23. We have isolated from this interval a novel gene, WASP, which is expressed in lymphocytes, spleen, and thymus. The gene is not expressed in two unrelated WAS patients, one of whom has a single base deletion that produces a frame shift and premature termination of translation. Two additional patients have been identified with point mutations that change the same arginine residue to either a histidine or a leucine. WASP encodes a 501 amino acid proline-rich protein that is likely to be a key regulator of lymphocyte and platelet function.
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PMID:Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. 800 Nov 29

Two commercially available expression vectors were modified to generate plasmids pGEXcPk and pQ9cPk. Proteins expressed from pGEXcPk and pQ9cPk had a short oligopeptide tag termed Pk at their carboxy termini and either glutathione S-transferase (GST) or a small histidine (His) tag, respectively, at their N termini. GST fusion proteins can be purified on immobilized glutathione and proteins coupled to the His tag selectively bind to Ni(2+)-NTA columns. The Pk tag is recognized by monoclonal antibody (MAb) SV5-P-k, previously produced in our laboratory. Thus proteins expressed from the pGEXcPk and pQ9cPk vectors can be purified in a two-step procedure, first via the N-terminal tag and second via the C-terminal tag. The combination of two affinity purification steps significantly improves the antigen purity and selects for full-size proteins. Moreover, by using the MAbSV5-P-k in the second purification step, Pk-linked antigens can be assembled directly into solid matrix-antibody-antigen (SMAA) complexes for use as vaccines. The genes for nef, endonuclease, p15, p17, p27, protease, Rev, reverse transcriptase (rt), tat, vif, vpr, and vpx of simian immunodeficiency virus (SIV mac 251) were cloned and expressed as both GST-SIV-Pk and His-SIV-Pk proteins. Multivalent SMAA complexes were made that contained His-p17-Pk, His-p27-Pk, His-rt-Pk, His-vpx-Pk, and His-vpr-Pk. Following two immunizations of mice with this mixture, antibodies could be detected to all five SIV antigens. When compared to single-protein immunizations, the immunogenicity of some of the proteins in this cocktail was either enhanced or decreased. Mice were also immunized with His-p17-Pk or His-p17-Pk-antibody complexes in the presence or absence of alum. The antibody-antigen complexes induced two- to four-fold higher antibody levels than antigen alone but did not appear to be more immunogenic in inducing lymphoproliferative responses. Sera from SIV-infected macaques were tested for the presence of antibodies reacting with the recombinant proteins by Western blot analysis. Antibodies to endonuclease, p15, p17, p27, rt, and vif were readily detected, antibodies against protease and vpx were present at much lower levels, but no antibodies were detected to nef, rev, tat, or vpr. Thus, we have developed a comprehensive range of reagents (available on request) that can be used to examine immune responses to SIV in both mice and monkeys.
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PMID:Expression and purification of nonglycosylated SIV proteins, and their use in induction and detection of SIV-specific immune responses. 807 30

Proteolytic experiments in conjunction with 1H-NMR spectroscopy show that the Nef (negative factor) protein from human immunodeficiency virus type 1 probably consists of two main domains, the N-terminal anchor domain at amino acid positions 2-65 and the C-terminal core domain at positions 66-206. The N-terminal domain is likely to be located at the surface of the protein, while the C-terminal domain has a compactly folded core and is stable in the absence of the anchor domain. It is conceivable that the core domain represents a functional domain of the Nef protein, activated after the removal of the membrane anchor by the human-immunodeficiency-virus protease or cellular proteases. Nef is stable at pH 5-12 and denatures at 317-322 K. The Nef protein remains in its native conformation in dimethyl-sulfoxide/water mixtures up to 35% (by vol.), and in acetonitrile/water up to 14% (by vol.). Nef refolds spontaneously after denaturation with urea or guanidinium hydrochloride. The 1H-NMR parameters and pKa values of five of the nine histidine residues and one of the seven tyrosine residues were determined and were found in four cases to be typical for residues which are not located in the interior of the protein.
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PMID:Stability and proteolytic domains of Nef protein from human immunodeficiency virus (HIV) type 1. 817 61


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