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)

Common variable immunodeficiency (CVI) patients are at high relative risk of developing non-Hodgkin lymphomas (NHL), mainly represented by B-lineage diffuse large cell lymphomas. The molecular pathogenesis and histogenesis of CVI-related NHL are poorly understood. We have thus attempted to provide a detailed molecular characterization of their histogenesis and pathogenesis. A panel of 5 CVI-related NHL was subjected to detailed analysis of histogenetic markers (mutations of immunoglobulin variable heavy chain-IgVH and of BCL-6 genes) acquired by B-cells at the time of germinal center transit. Somatic hypermutation of IgVH and BCL-6 genes occurred in 5/5 cases; in all cases, mutations were stable with no evidence of ongoing mutation processes. In 3/5 cases, the pattern of IgVH mutations was consistent with selection and stimulation of the tumor clone by antigen. To further clarify the pathogenesis, samples were tested for inactivation by promoter hypermethylation of the genes 0(6)-methylguanine-DNA-methyltransferase (MGMT) and glutathione S-transferase (GST) p1, which code for detoxifying enzymes, as well as of death-associated protein (DAP)-kinase, coding for a proapoptotic molecule. Promoter hypermethylation of MGMT, GSTp1 and DAP-kinase was detected in 2/5, 3/5 and 3/5 CVI-related NHL, respectively. Overall, these data indicate that: i) similarly to other immunodeficiency-related NHL, CVI-related NHL derive from germinal center-related B-cells, namely centrocytes or post-germinal center B-cells; ii) antigen stimulation and selection are involved in the development of at least a fraction of these cases; iii) hypermethylation of the MGMT, DAP-kinase and GSTp1 genes occurs at sustained frequencies in CVI-related NHL and may provide novel prognostic markers and therapeutic targets for the clinical management of these lymphomas.
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PMID:Molecular characterization of common variable immunodeficiency-related lymphomas. 1169 5

The Wnt signaling pathway plays an important role in neural cell development and function. The key components of this pathway, beta-catenin and its partner TCF-4/LEF-1, exert their effects on transcription by entering the nuclei, where they associate with the TCF-4/LEF-1 DNA motif positioned in the promoters of several important genes. Here we examined the role of TCF-4 upon transcription of the human immunodeficiency virus type 1 (HIV-1) promoter in human astrocytic cells. Our results showed that expression of TCF-4 in human astrocytic cells (U-87MG cells) decreased the basal and Tat-mediated transcription of the HIV-1 long terminal repeat (LTR). Results from promoter deletion studies revealed that the promoter sequence of the LTR with no classical binding motif for TCF-4/LEF-1, which spans positions -80 to +80 of the LTR, remained responsive to down-regulation by TCF-4. Noticeably, removal of the sequences between positions -80 and -68 decreased the negative effect of TCF-4 on viral gene transcription. A mutant variant of TCF-4 with no binding site for beta-catenin was able to down-regulate LTR transcription, suggesting that beta-catenin may not be directly involved in the observed regulatory events. Results from the glutathione S-transferase pull-down assay as well as the combined immunoprecipitation and Western blot analysis of protein extract from U-87MG cells revealed an interaction of Tat with TCF-4. Subcellular examination of TCF-4 and Tat in cells expressing either protein alone showed a predominantly nuclear accumulation of these proteins. However, in cells which coexpressed both TCF-4 and Tat, significant levels of these proteins were found in the cytoplasm. All together, these observations provide evidence for the cooperative interaction of TCF-4, the important transcription factor of the Wnt pathway, with Tat; this interaction may determine the level of viral gene transcription in human astrocytic cells.
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PMID:Evidence for regulation of long terminal repeat transcription by Wnt transcription factor TCF-4 in human astrocytic cells. 1236 61

Human immunodeficiency virus 1 (HIV-1) encodes a gene product, Vpr, that facilitates the nuclear uptake of the viral pre-integration complex in non-dividing cells and causes infected cells to arrest in the G(2) phase of the cell cycle. Vpr was also shown to cause mitochondrial dysfunction in human cells and budding yeasts, an effect that was proposed to lead to growth arrest and cell killing in budding yeasts and apoptosis in human cells. In this study, we used a genetic selection in Saccharomyces cerevisiae to identify hexameric peptides that suppress the growth arrest phenotype mediated by Vpr. Fifteen selected glutathione S-transferase (GST)-fused peptides were found to overcome to different extents Vpr-mediated growth arrest. Amino acid analysis of the inhibitory peptide sequences revealed the conservation of a di-tryptophan (diW) motif. DiW-containing GST-peptides interacted with Vpr in GST pull-down assays, and their level of interaction correlated with their ability to overcome Vpr-mediated growth arrest. Importantly, Vpr-binding GST-peptides were also found to alleviate Vpr-mediated apoptosis and G(2) arrest in HIV-1-producing CD4(+) T cell lines. Furthermore, they co-localized with Vpr and interfered with its nuclear translocation. Overall, this study defines a class of diW-containing peptides that inhibit HIV-1 Vpr biological activities most likely by interacting with Vpr and interfering with critical protein interactions.
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PMID:Genetic selection of peptide inhibitors of human immunodeficiency virus type 1 Vpr. 1237 52

Feline immunodeficiency virus (FIV), like other members of the lentivirus subfamily, such as human immunodeficiency virus type 1 (HIV-1), can infect nondividing and terminally differentiated cells. The transport of the preintegration complex into the nucleus is cell cycle-independent, but the mechanism is not well understood. Integrase is a key component of the complex and has been suggested to play a role in nuclear import during HIV-1 replication. To determine its karyophilic property, FIV integrase fused with glutathione S-transferase and enhanced green fluorescent protein was expressed in various feline and human cells and the subcellular localization was visualized by fluorescence microscopy. Wild-type FIV integrase was karyophilic in all cell lines tested and capable of targeting the fusion protein to the nuclei of transfected cells. Analysis of deletion and point mutation variants of FIV integrase failed to reveal any canonical nuclear localization signal, and the karyophilic determinant was mapped to the highly conserved N-terminal zinc-binding HHCC motif. A region near the C-terminal domain enriched with basic amino acid residues also affected the nuclear import of integrase. However, the role of this region is only modulatory in comparison to that of the zinc-binding domain. The N-terminal zinc-binding domain does not bind DNA and instead is essential in integrase multimerization. We therefore postulate that the karyophilic property of FIV integrase requires subunit multimerization promoted by the HHCC motif. Alternatively, the HHCC motif may directly promote interaction between FIV integrase and cellular proteins involved in nuclear import.
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PMID:Subcellular localization of feline immunodeficiency virus integrase and mapping of its karyophilic determinant. 1266 58

Protein transduction domains (PTDs) derived from human immunodeficiency virus Tat protein and herpes simplex virus VP22 protein are useful for the delivery of non-membrane-permeating polar or large molecules into living cells. In the course of our study aiming at evaluating PTD, we unexpectedly found that the fluorescent-dye-labeled glutathione S-transferase (GST) from Schistosoma japonicum without known PTDs was delivered into COS7 cells. The intracellular transduction of GST was also observed in HeLa, NIH3T3, and PC12 cells, as well as in hippocampal primary neurons, indicating that a wide range of cell types is permissive for GST transduction. Furthermore, we showed that the immunosuppressive peptide VIVIT fused with GST successfully inhibits NFAT activation. These results suggest that GST is a novel PTD which may be useful in the intracellular delivery of biologically active molecules, such as small-molecule drugs, bioactive peptides, or proteins.
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PMID:Intracellular delivery of glutathione S-transferase into mammalian cells. 1276 35

The Vpr (viral protein R) of human immunodeficiency virus, type 1, which is expressed during the late stage of the viral infection, has received special attention because of its ability to control transcription of the human immunodeficiency virus, type 1, long terminal repeat and to influence cell cycle progression. Here we demonstrate that Vpr has the ability to regulate transcription of the cyclin-dependent kinase inhibitor, p21(WAF1) (p21), one of the key regulators of the cell cycle, in human astrocytic cells. The results from transcription assays demonstrated that Vpr augments promoter activity of p21 through the GC-rich region located between nucleotides -84 and -74 with respect to the +1 transcription start site. Activation of p21 by Vpr required cooperativity of Sp1, which binds to the DNA sequence spanning -84 to -74. Results from bandshift assay revealed an increased level of Sp1 DNA binding activity in the presence of Vpr. Furthermore, Vpr was able to associate with Sp1 via the zinc finger domain located in the C-terminal region of Sp1. Functional studies revealed that the cooperativity between Vpr and Sp1 requires the zinc finger domain at the C terminus and the glutamine-rich domain at the N terminus of Sp1. Expression of p53 further enhanced the level of Vpr-Sp1-mediated transcription activation of p21 through the sequence spanning -84 to -74 and increased the DNA binding activity of Sp1 in the presence of Vpr. Results from glutathione S-transferase pull-down assay showed the association of Vpr with p53 in extracts containing Sp1. Altogether, the outcome of our functional and binding studies suggested that the physical interaction of Vpr with Sp1 and p53 could modulate transcriptional activity of p21.
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PMID:Interplay between HIV-1 Vpr and Sp1 modulates p21(WAF1) gene expression in human astrocytes. 1530 82

Viral protein R (Vpr) of human immunodeficiency virus type 1 has potent karyophilic properties, but details of the mechanism by which it enters the nucleus remain to be clarified. We reported previously that two regions, located between residues 17 and 34 (alphaH1) and between residues 46 and 74 (alphaH2), are indispensable for the nuclear localization of Vpr. Here, we reveal that a chimeric protein composed of the nuclear localization signal of Vpr, glutathione S-transferase, and green fluorescent protein was localized at the nuclear envelope and then entered the nucleus upon addition of importin-alpha. An in vitro transport assay using a series of derivatives of importin-alpha demonstrated that the carboxyl terminus was required for this nuclear import process. We also showed that Vpr interacts with importin-alpha through alphaH1 and alphaH2; only the interaction via alphaH1 is indispensable for the nuclear entry of Vpr. These observations indicate that importin-alpha functions as a mediator for the nuclear entry of Vpr.
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PMID:Importin-alpha promotes passage through the nuclear pore complex of human immunodeficiency virus type 1 Vpr. 1573 Dec 50

Infection of the oral mucosa of human immunodeficiency virus type 1 (HIV-1)-infected individuals remains an under-evaluated and somewhat enigmatic process. Nonetheless, it is of profound importance in the ongoing AIDS pandemic, based on its potential as a site of person-to-person transmission of the virus as well as a location of HIV-1 pathogenesis and potential reservoir of disease in the setting of virally suppressive highly active antiretroviral therapy. We utilized molecular and virological techniques to analyze HIV-1 infection of primary human mucosal cells and also evaluated the proapoptotic potential of selected HIV-1 proteins in primary isolated human oral keratinocytes. Primary isolated human oral keratinocytes were plated on 0.4 microM polyethylenetetraphthalate cell culture inserts to form an in vitro oral mucosal layer. The strength of this layer in forming a barrier was determined by measuring trans-epithelial electrical current passage across the monolayer. The oral keratinocyte monolayers had trans-epithelial electrical resistance of approximately 176 to 208 omega. For viral infectivity assays, the macrophage-tropic (R5) HIV-1 strains, YU-2 and ADA, and T-cell-line-tropic (X4), NL4-3 virions, incubated with or without deoxynucleoside triphosphates (dNTPs) and/or the polyamines spermine and spermidine, were used to infect oral keratinocytes. Of importance, polyamines and dNTPs have been shown to enhance natural endogenous reverse transcription (NERT), a step essential for early lentiviral infection, and are abundantly present in human semen. The infectivities of HIV-1 strains YU-2, ADA, and NL4-3 for these primary keratinocytes were dramatically increased by the addition of physiological concentrations of dNTPs, spermine, and spermidine. Binding and viral internalization assay studies showed no differences in these oral mucosal cells, with or without NERT-altering agents. It was also observed that the recombinant, cell-free HIV-1 proteins Nef, Tat, and gp120 (R5) induced apoptosis in primary oral keratinocytes compared with the results seen with nontreated cells or cells treated with glutathione S-transferase protein as a control under similar conditions. Microarray analyses suggested that HIV-1 gp120 and Tat induce apoptosis in primary human oral keratinocytes via the Fas/FasL apoptotic pathway, whereas induction of apoptosis by Nef occurs through both Fas/FasL and mitochondrial apoptotic pathways. Thus, these findings suggest molecular mechanisms by which semen in particular, as well as other bodily fluids such as cervicovaginal secretions, could increase oral transmission of HIV-1 via increasing infectivity in confluent and low-replicating oral keratinocytes. As well, the induction of apoptosis in human oral keratinocytes with relevant HIV-1-specific proteins suggests another potential complementary mechanism by which the oral mucosa barrier may be disrupted during HIV-1 infection in vivo.
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PMID:Molecular interactions of human immunodeficiency virus type 1 with primary human oral keratinocytes. 1595 88

The high mutation rate of HIV-1 (human immunodeficiency virus-1) is a major obstacle to developing an effective vaccine. The mutation of ELDKWA-(aa669-674) to ELDEWA-epitope on HIV-1 gp41 caused the immune escape from neutralization by potent anti-HIV-1 human monoclonal antibody (mAb) 2F5. In this study, we suggested and evaluated a multi-epitope vaccine as a new strategy to develop HIV-1 vaccines. A glutathione S-transferase (GST) fusion protein (GST-K8E8) containing 8 copies of ELDKWA-and mutated ELDEWA-epitopes was constructed and used to immunize mice or rabbits. Analysis of the antisera (rAS3) induced by GST-K8E8 suggested that multi-epitope vaccine immunogen could raise antibodies in mice and rabbits against either the original ELDKWA-epitope or the mutated ELDEWA-epitope that resulted in immune escape. Briefly, ELDKWA-epitope-specific antibodies, directly purified from rAS3 by ELDKWA-epitope-peptide affinity chromatography, recognized either original gp41 protein (ELDKWA, rgp41K) or mutated gp41 (ELDEWA, rgp41E) in immunoblotting assay; in contrast, the existing ELDKWA-epitope antibodies recognized only rgp41K but not rgp41E, which were purified by ELDKWA-epitope-peptide affinity chromatography from rAS3 that were firstly completely pre-absorbed by ELDEWA-epitope-peptide affinity beads. And the same results were also observed when detecting the ELDEWA-epitope-specific antibodies in rAS3 by a means similar to the above. All the data presented here demonstrated that a high density multi-epitope vaccine could be an interesting strategy against HIV-1 mutation.
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PMID:The recombinant immunogen with high-density epitopes of ELDKWA and ELDEWA induced antibodies recognizing both epitopes on HIV-1 gp41. 1611 99

Nef, an accessory protein of human and simian immunodeficiency viruses, is a critical determinant of pathogenesis that promotes the progression from infection to AIDS. The pathogenic effects of Nef are in large part dependent on its ability to downregulate the macrophage and T-cell coreceptor, CD4. It has been proposed that Nef induces downregulation by linking the cytosolic tail of CD4 to components of the host-cell protein trafficking machinery. To identify these components, we developed a novel Nef-CD4 downregulation system in Drosophila melanogaster S2 cells. We found that human immunodeficiency virus type 1 (HIV-1) Nef downregulates human CD4 in S2 cells and that this process is subject to the same sequence requirements as in human cells. An RNA interference screen targeting protein trafficking genes in S2 cells revealed a requirement for clathrin and the clathrin-associated, plasma membrane-localized AP2 complex in the downregulation of CD4. The requirement for AP2 was confirmed in the human cell line HeLa. We also used a yeast three-hybrid system and glutathione S-transferase pull-down analyses to demonstrate a robust, direct interaction between HIV-1 Nef and AP2. This interaction requires a dileucine motif in Nef that is also essential for downregulation of CD4. Together, these results support a model in which HIV-1 Nef downregulates CD4 by promoting its accelerated endocytosis by a clathrin/AP2 pathway.
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PMID:Downregulation of CD4 by human immunodeficiency virus type 1 Nef is dependent on clathrin and involves direct interaction of Nef with the AP2 clathrin adaptor. 1726


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