Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The envelope glycoprotein (gp120/41) of the human immunodeficiency virus (HIV-1) attaches the virus to the cellular CD4 receptor and mediates virus entry into the cytoplasm. In addition to being required for formation of infectious HIV, expression of gp120/41 at the plasma membrane causes the cytopathic fusion of cells carrying the CD4 antigen. The expression of gp120/41 is therefore an ideal target for therapeutic strategies designed to combat AIDS. Here we show that expression of a soluble CD4 molecule, mutated to contain a specific retention signal for the endoplasmic reticulum, blocks secretion of gp120 and surface expression of gp120/41, but does not interfere with transport of wild-type CD4. By blocking transport of the HIV glycoprotein, this retained CD4 molecule prevents the fusion of CD4 cells that is normally caused by the HIV glycoprotein. Expression of the retained CD4 molecule in human T cells might therefore be useful in the intracellular immunization procedure suggested by Baltimore.
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PMID:Prevention of HIV-1 glycoprotein transport by soluble CD4 retained in the endoplasmic reticulum. 234 70

The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) plays a major role in the down-regulation of its receptor, CD4. Using a transient-expression system, we investigated the interaction of the HIV-1 envelope glycoprotein with CD4 during their movement through the intracellular membrane traffic. In singly transfected cells, the envelope glyprotein gp160 was synthesized, glycosylated, and localized predominantly in the endoplasmic reticulum. Only a minor fraction of gp160 was proteolytically cleaved, producing gp120 and gp41, and gp120 was secreted into the medium. On the other hand, the CD4 molecule, when expressed alone, was properly glycosylated and transported efficiently to the cell surface. However, when gp160 and CD4 were coexpressed in the same cell, the cell surface delivery of CD4 was greatly reduced. In coexpressing cells, CD4 formed a specific intracellular complex with gp160 as both proteins could be immunoprecipitated by antibodies against either the gp160 or CD4 (OKT4) but not by OKT4A, a blocking antibody against CD4. The specific gp160-CD4 complex was localized predominantly in the endoplasmic reticulum, and the CD4 in the complex did not acquire endoglycosidase H resistance. The present studies demonstrated that a specific intracellular interaction between gp160 and CD4 was responsible for the cell surface down-regulation of CD4 in cells expressing both the envelope glycoprotein of HIV-1 and its receptor, CD4.
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PMID:Intracellular interaction of human immunodeficiency virus type 1 (ARV-2) envelope glycoprotein gp160 with CD4 blocks the movement and maturation of CD4 to the plasma membrane. 224 95

The ultrastructural changes in the jejunal mucosa of 11 male patients, three with clinical AIDS, five with AIDS related complex-progressive generalized lymphadenopathy (ARC-PGL), and three who were only HIV antibody positive, were studied. In the enterocytes, major abnormalities were proliferation of smooth endoplasmic reticulum mitochondrial changes, vacuolization of cells, and fat hold up. In the lamina propria, degeneration of enteric nerve axons and smooth muscle were seen. Microvasculature showed both endothelial cell degeneration and hyperplasia. The presence of tubuloreticular inclusions in endothelial cells paralleled the stage of the disease. Since none of the 11 patients had any opportunistic infection, these changes are likely to be the effect of HIV infection.
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PMID:Ultrastructure of the jejunal mucosa in human immunodeficiency virus infection. 238 Aug 6

The intracellular processing of the gp160 HIV-1 envelope precursor was characterized in acutely infected CD4+ T cells. Our data show that gp160 undergoes endoproteolytic cleavage by a nonacid dependent protease(s) in the rough endoplasmic reticulum-Golgi complex, within cis or medial cisternae, and is not transported to the cell surface. Two-dimensional electrophoretic pulse-chase analysis indicates that it takes greater than 2 h for gp160 to be transported from the rough endoplasmic reticulum to the site of action of sialyltransferases in the trans Golgi. Evidence is presented that gp160 is subject to mannose trimming in the Golgi complex, which is inhibited by 1-deoxymannojirimycin (a specific Golgi alpha-mannosidase I inhibitor). Preliminary data also suggest that gp120 is post-translationally modified by sialylated O-linked oligosaccharides.
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PMID:Intracellular processing of the gp160 HIV-1 envelope precursor. Endoproteolytic cleavage occurs in a cis or medial compartment of the Golgi complex. 240 37

The processing and maturation of envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) were studied in infected cells treated with inhibitors of oligosaccharide processing. In MOLT-3 cells chronically infected with HIV-1 (strain HTLV-IIIB), tunicamycin severely inhibited the glycosylation of envelope proteins. Deoxynojirimycin, an inhibitor of glucosidase I in the rough endoplasmic reticulum, inhibited the proteolytic processing of gp160, whereas no such effect was noted with either deoxymannojirimycin or swainsonine, inhibitors of mannosidase I and II, respectively, in the Golgi complex. The processed gp120 and gp41 synthesized in the presence of deoxymannojirimycin were found to contain mannose-rich oligosaccharide cores as evidenced by their susceptibility to endoglycosidase H digestion. The formation of syncytia normally observed when CEM cells are cocultured with HIV-1-infected cells was markedly inhibited in the presence of deoxynojirimycin, but such inhibition was not observed in cells treated with deoxymannojirimycin or swainsonine. The infectivity of virions released from MOLT-3/HTLV-IIIB cells treated with deoxynojirimycin or deoxymannojirimycin was significantly lower than the infectivity of virions released from untreated cells. On the other hand, treatment with swainsonine did not affect the infectivity of the progeny virus. These results suggest that the proteolytic processing of gp160 takes place in infected cells when the glycoprotein has mannose-rich oligosaccharide structures. Trimming of glucose residues and the primary trimming of mannose residues are necessary for the release of infectious virus.
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PMID:Role of oligosaccharides in the processing and maturation of envelope glycoproteins of human immunodeficiency virus type 1. 254 46

HIV-1 Vpu is a small transmembrane phosphoprotein of 16 kDa which performs critical roles in CD4 proteolysis and virus release. Previous studies have demonstrated that Vpu-induced degradation of CD4 occurs in the endoplasmic reticulum (ER), and that the proteolytic process is sequence specific requiring both the transmembrane and cytoplasmic domains of CD4. In the present study, we investigated the effects of Vpu expression on the intracellular membrane trafficking pathway of mammalian cells. In singly transfected cells, the HIV envelope glycoproteins and vesicular stomatitis virus glycoprotein (VSV G) were properly transported to the cell surface undergoing oligosaccharide modifications characteristic of their movement through the Golgi complex. In contrast, the cell surface delivery of glycoproteins was severely impeded in cells expressing Vpu. Biochemical analyses revealed that Vpu expression blocked the transfer of proteins from the ER-Golgi complex to the plasma membrane in a dose- and protein-dependent manner. Soluble gp120 exhibited extreme transport defects in the presence of Vpu, whereas transmembrane proteins (e.g., gp160, VSV) responded only moderately to wild-type Vpu. To gain insight into Vpu-mediated transport inhibition, we performed mutational analysis of the CK-2 phosphorylation sites (serines at 52 and 56) in the Vpu protein. CK-2 phosphorylation of Vpu has been shown to regulate the activity of the protein in reactions that involve the proteolysis of CD4 in the ER. We demonstrate here that the phosphorylation mutant is defective in both sequence-specific degradation of VRE-containing substrates and the transport inhibition of gp120 and VSV-G in the secretory pathway. Thus, these experiments have revealed that Vpu-mediated proteolysis and transport inhibition are mechanistically coupled requiring the same structural elements of the Vpu protein in both processes. We propose that the primary effect of Vpu expression is to impede the secretion process and then access glycoproteins bearing the VRE for Vpu-mediated proteolysis in the ER of mammalian cells.
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PMID:The human immunodeficiency virus type 1 Vpu protein: a potential regulator of proteolysis and protein transport in the mammalian secretory pathway. 749 87

The lysis of virally infected cells by CTLs requires the recognition of processed fragments of viral proteins presented in association with class I MHC molecules on the surfaces of infected cells. Processing begins in the cytosol with the degradation of viral proteins into peptides that are then transported into the endoplasmic reticulum (ER) for association with newly synthesized class I molecules. Transport is mediated by a heterodimer of the MHC-encoded proteins, transporter associated with Ag presentation (TAP)-1 and TAP-2. Uncertainty exists over the site of processing of viral envelope (env) proteins. The extracellular domains of env proteins are not present in the cytosol, the site in which the class I-restricted Ag-processing pathway begins. Rather, the ecto-domains of env proteins are cotranslationally translocated into the ER during biosynthesis. We have analyzed the processing of the HIV-1 env protein by using a large series of env-specific human CD8+ CTL clones. These studies have led to the delineation of two distinct processing pathways. The first pathway permits a subset of class I-restricted epitopes in the ecto-domain of the env protein to be generated efficiently by a TAP-1/2-independent mechanism localized to the ER or a premedial Golgi compartment. A second, more general pathway that is capable of generating all env epitopes uses as a substrate env protein mislocalized to the cytosol and produces peptides that are transported from the cytoplasm to the ER in a TAP-1/2-dependent fashion.
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PMID:An epitope-selective, transporter associated with antigen presentation (TAP)-1/2-independent pathway and a more general TAP-1/2-dependent antigen-processing pathway allow recognition of the HIV-1 envelope glycoprotein by CD8+ CTL. 753 43

Calcium depletion from the endoplasmic reticulum inhibits protein synthesis and correlates with increased phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha) by a mechanism that does not require ongoing protein synthesis. To elucidate whether protein synthesis inhibition requires eIF-2 alpha phosphorylation and whether eIF-2 alpha phosphorylation is mediated by the double-stranded RNA-dependent protein kinase (PKR), we studied protein synthesis in response to calcium depletion mediated by calcium ionophore A23187 in cell lines overexpressing wild-type eIF-2 alpha, a mutant eIF-2 alpha (S51A) that is resistant to phosphorylation, or a dominant negative mutant PKR (K296P in catalytic subdomain II). Expression of either mutant eIF-2 alpha or mutant PKR partially protected NIH3T3 cells from inhibition of protein synthesis upon A23187 treatment. In contrast, overexpression of wild-type PKR increased sensitivity to protein synthesis inhibition mediated by A23187 treatment. In a COS-1 monkey cell transient transfection system, increased eIF-2 alpha phosphorylation in response to A23187 treatment was inhibited by expression of the dominant negative PKR mutant. Overexpression of the PKR regulatory RNA binding domain, independent of the PKR catalytic domain, was sufficient to inhibit increased phosphorylation of eIF-2 alpha upon A23187 treatment. In addition, overexpression of the HIV TAR RNA binding protein also inhibited eIF-2 alpha phosphorylation upon A23187 treatment. Taken together, our data show that calcium depletion activates PKR to phosphorylate eIF-2 alpha, and this activation is likely mediated through the PKR RNA binding domain.
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PMID:Calcium depletion from the endoplasmic reticulum activates the double-stranded RNA-dependent protein kinase (PKR) to inhibit protein synthesis. 762 70

Liposomes have been proposed as vehicles for vaccines against parasitic and viral illnesses. Experimental vaccines against malaria, HIV, hepatitis A, and influenza virus have been shown to be safe and highly immunogenic in several human trials. Analysis of the intracellular trafficking patterns of liposomal antigen reveals that after being phagocytosed by macrophages, liposomal antigen readily escapes from endosomes into the cytoplasm of the macrophages. It is proposed that liposomal peptide antigen can enter either the Golgi apparatus or the endoplasmic reticulum and thereby interact with MHC class II or class I molecules. The intracellular cytoplasmic trafficking patterns of liposomal antigens raise the possibility that liposomes may have utility in human vaccines for induction of either humoral immunity or cytotoxic T lymphocytes.
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PMID:Liposomal vaccines: clinical status and immunological presentation for humoral and cellular immunity. 762 48

The ability of minigene-encoded viral peptide epitopes to be presented by class I molecules in the absence of MHC-encoded transporters has been evaluated in mutant T2 cells. These cells have a large deletion in the class II MHC region that includes the known transporter protein for antigenic peptides and proteasome genes and they are defective in presenting viral epitopes to CTL. T2 cells that express minigenes encoding the influenza virus matrix peptide 58-66 (GILGFVFTL) and two HTLV 1 Tax peptides 11-19 (LLFGYPVYV) and 12-19 were lysed by HLA-A2-restricted peptide-specific CTL. Minigene expression of a HLA-A2-restricted HIV reverse transcriptase peptide 476-484 (ILKEPVHGV) with three charged residues sensitized T2 cells poorly for lysis by HIV-specific CTL unless the peptide was preceded by an endoplasmic reticulum translocation signal sequence. Expression of an influenza virus nucleoprotein peptide 383-391 (SRYWAIRTR) with three charged arginine residues did sensitize HLA-B27+ T2 cells for lysis by peptide-specific CTL. These and other results with endogenously expressed peptide analogs in which hydrophobic and charged amino acids were interchanged demonstrate that antigenic peptides can be translocated from the cytoplasm into the class I Ag presentation pathway independent of MHC-encoded transporters; and that peptide hydrophobicity appears not to be a major determinant in selecting peptides for this alternate pathway.
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PMID:Presentation of endogenous peptides to MHC class I-restricted cytotoxic T lymphocytes in transport deletion mutant T2 cells. 767 94


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