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:C0038362 (stomatitis)
8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this report, we describe a crucial role of lipid raft-colocalized receptors in the entry of human immunodeficiency virus type 1 (HIV-1) into CD4(+) T cells. We show that biochemically isolated detergent-resistant fractions have characteristics of lipid rafts. Lipid raft integrity was required for productive HIV-1 entry as determined by (i) semiquantitative PCR analysis and (ii) single-cycle infectivity assay using HIV-1 expressing the luciferase reporter gene and pseudotyped with HIV-1 HXB2 envelope or vesicular stomatitis virus envelope glycoprotein (VSV-G). Depletion of plasma membrane cholesterol with methyl-beta-cyclodextrin (MbetaCD) relocalized raft-resident markers to a nonraft environment but did not significantly change the surface expression of HIV-1 receptors. MbetaCD treatment inhibited productive infection of HIV-1 by 95% as determined by luciferase activity in cells infected with HXB2 envelope-pseudotyped virus. In contrast, infection with VSV-G-pseudotyped virus, which enters the cells through an endocytic pathway, was not suppressed. Biochemical fractionation and confocal imaging of HIV-1 receptor distribution in live cells demonstrated that CD4, CCR5, and CXCR4 colocalized with raft-resident markers, ganglioside GM1, and glycosylphosphatidylinositol-anchored CD48. While confocal microscopy analysis revealed that HIV-1 receptors localized most likely to the same lipid microdomains, sucrose gradient analysis of the receptor localization showed that, in contrast to CD4 and CCR5, CXCR4 was associated preferentially with the nonraft membrane fraction. The binding of HIV-1 envelope gp120 to lipid rafts in the presence, but not in the absence, of cholesterol strongly supports our hypothesis that raft-colocalized receptors are directly involved in virus entry. Dramatic changes in lipid raft and HIV-1 receptor redistribution were observed upon binding of HIV-1 NL4-3 to PM1 T cells. Colocalization of CCR5 with GM1 and gp120 upon engagement of CD4 and CXCR4 by HIV-1 further supports our observation that HIV-1 receptors localize to the same lipid rafts in PM1 T cells.
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PMID:Human immunodeficiency virus type 1 uses lipid raft-colocalized CD4 and chemokine receptors for productive entry into CD4(+) T cells. 1196 88

Human immunodeficiency virus (HIV) gp120 induces multiple cellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3-kinase) pathway. The role of the PI3-kinase pathway in HIV-1 replication is not understood. Here we examined whether HIV-1 gp120 upregulates the PI3-kinase pathway and whether PI3-kinase activity plays a role in virus replication in primary human CD4(+) T cells and macrophages. Soluble and virion-associated HIV-1 gp120 induced calcium mobilization and phosphorylation of the PI3-kinase downstream effectors PKB/Akt and p70 S6 kinase. gp120-induced PI3-kinase activity and calcium mobilization were inhibited by pertussis toxin and blocking antibodies directed against CCR5 and CXCR4, suggesting that the signaling is mediated through the chemokine receptor. The PI3-kinase inhibitor LY294002 inhibited infection of CD4(+) T cells and macrophages with X4 and R5 HIV-1-pseudotyped viruses at concentrations that did not induce cell toxicity or downregulate HIV-1 coreceptor expression. When gp120-induced signaling was bypassed with the vesicular stomatitis virus G envelope protein, infection was still sensitive to PI3-kinase inhibition, suggesting that basal PI3-kinase activity is required for infection. LY294002 inhibited HIV-1 infection when added after viral entry and did not affect formation of the HIV-1 reverse transcriptase products R/U5 and long terminal repeat/Gag in the presence of the inhibitor. However, when the inhibitor was added after viral integration had occurred, no inhibition of HIV infection was observed. Our studies show that inhibition of the PI3-kinase signaling pathway suppresses virus infection post-viral entry and post-reverse transcription but prior to HIV gene expression. This type of host-virus interaction has implications for anti-HIV therapeutics that target cellular signaling machinery.
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PMID:Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages. 1255 92

We investigated the effects of signaling through CD28 family molecules on human immunodeficiency virus type 1 (HIV-1) replication in vitro. A monoclonal antibody (mAb) specific for inducible costimulator (ICOS) suppressed both X4 and R5 HIV-1 replication in CD4(+) peripheral blood mononuclear cells (PBMC). This suppression was not attributable to reduced cell growth or viability. CD28 mAb showed variable effects and also suppressed HIV-1 replication when immobilized. Replication of pseudotype viruses with HIV-1-but not with vesicular stomatitis virus G-envelope was efficiently suppressed in CD4(+) PBMC treated with ICOS or CD28 mAbs. However, CD4, CXCR4, and CCR5 expression on the surface was not down-regulated. Moreover, HIV-1 replication in CD4(+) PBMC was suppressed by a soluble form of human B7-H2, a ligand of ICOS, but was enhanced by soluble B7-1, a ligand for CD28. These findings suggest that natural or artificial ligands for ICOS potentially suppress HIV-1 replication mainly at the entry stages.
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PMID:Inducible-costimulator-mediated suppression of human immunodeficiency virus type 1 replication in CD4(+) T lymphocytes. 1524 65

We previously demonstrated that human immunodeficiency virus type 1 (HIV-1) infection is nonrandom and that double infection occurs more frequently than predicted from random events. To probe the possible mechanisms for nonrandom infection, we examined the role of HIV-1 entry pathways by using viruses pseudotyped with either CCR5-tropic HIV-1 Env or vesicular stomatitis virus G protein (VSV G). These two proteins use different receptors and entry pathways. We found that regardless of the protein used, double infection occurred more frequently than random events, indicating nonrandom HIV-1 infection in both entry pathways. However, the frequency of double infection differed significantly, depending on the envelope protein. In primary CD4(+) T cells, double infection occurred most frequently when both viruses had CCR5-tropic HIV-1 Env and least frequently when the two viruses had different envelopes. These results indicated that the preference in virus entry was a significant but not the only factor contributing to nonrandom double infection. Furthermore, we demonstrated that the CD4 expression level in primary T cells affects their susceptibility to CCR5-tropic HIV-1 infection but not VSV G-pseudotyped HIV-1 infection. We have also examined infection with two viruses pseudotyped with CCR5- or CXCR4-tropic HIV-1 Env and have found that double infection occurred more frequently than random events. These results indicate that coreceptor usage is not a barrier to recombination between the two virus populations. In our previous study, we also demonstrated nonrandom double infection via dendritic cell (DC)-mediated HIV-1 transmission. To test our hypothesis that multiple HIV-1 virions are transmitted during DC-T-cell contact, we used two populations of DCs, each capturing one vector virus, and added both DC populations to T cells. We observed a decreased frequency of double infection compared with experiments in which DCs captured both viruses simultaneously. Therefore, these results support our hypothesis that multiple virions are transmitted from DCs to T cells during cell-mediated HIV-1 transmission.
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PMID:Mechanisms of nonrandom human immunodeficiency virus type 1 infection and double infection: preference in virus entry is important but is not the sole factor. 1576 15

We recently showed that both replicating and resting cells cultivated with ganciclovir (GCV) were killed when challenged with vesicular stomatitis virus G glycoprotein pseudotyped HIV-1-based virus-like particles (VLPs) carrying the Nef7 (i.e., an HIV-1 Nef mutant incorporating in virions at high levels)/herpes simplex virus-1 thymidine kinase (HSV-TK) fusion product. On this basis, a novel anti-HIV therapeutic approach based on Nef7/TK VLPs expressing X4 or R5 HIV cell receptor complexes has been attempted. We here report that (CD4-CXCR4) and (CD4-CCR5) Nef7-based VLPs efficiently enter cells infected by X4- or R5-tropic HIV-1 strains, respectively. Importantly, the delivery of the VLP-associated Nef7/TK led to cell death upon GCV treatment. Of interest, VLPs were effective also against non-replicating, HIV-1-infected primary human monocyte-derived macrophages. HIV-targeted VLPs represent a promising candidate for the treatment of persistently HIV-1-infected cells that are part of virus reservoirs resistant to HAART therapies.
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PMID:Selective elimination of HIV-1-infected cells by Env-directed, HIV-1-based virus-like particles. 1627 41

The infection of cultured monocyte-derived dendritic cells (DCs) with HIV-1 involves CD4 and CCR5 receptors, while transmission to T cells is enhanced at least in part by the lectin DC-SIGN/CD209. In the present study, we studied BDCA-1+ myeloid DCs isolated directly from human blood. These cells express CD4 and low levels of CCR5 and CXCR4 coreceptors, but not DC-SIGN. The myeloid DCs replicate two R5 viruses, BaL and YU2, and transfer infection to activated T cells. The virus productively infects a small fraction of the blood DCs that fail to mature in culture, as indicated by the maturation markers CD83 and DC-LAMP/CD208, and the expression of high CD86 and MHC class II, in contrast to many noninfected DCs. A greater proportion of BDCA-1+ DCs are infected when the virus is pseudotyped with the vesicular stomatitis envelope VSV-G (5-15%), as compared with the R5 virus (0.3-3.5%), indicating that HIV-1 coreceptors may limit the susceptibility of DCs to become infected, or the endocytic route of viral entry used by HIV/vesicular stomatitis virus enhances infectivity. When infected and noninfected cells are purified by cell sorting, the former uniformly express HIV p24 gag and are virtually inactive as stimulators of the allogeneic MLR, in contrast to potent stimulation by noninfected DCs from the same cultures. These results point to two roles for a small fraction of blood DCs in HIV-1 pathogenesis: to support productive infection and to evade the direct induction of T cell-mediated immunity.
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PMID:HIV-1 selectively infects a subset of nonmaturing BDCA1-positive dendritic cells in human blood. 1639 85

Human immunodeficiency virus type 1 (HIV-1) infection of human macrophages can be inhibited by antibodies which bind to the tetraspanin protein CD63, but not by antibodies that bind to other members of the tetraspanin family. This inhibitory response was limited to CCR5 (R5)-tropic virus and was only observed using macrophages, but not T cells. Here, we show that recombinant soluble forms of the large extracellular domain (EC2) of human tetraspanins CD9, CD63, CD81, and CD151 produced as fusion proteins with glutathione S-transferase (GST) can all potently and completely inhibit R5 HIV-1 infection of macrophages with 50% inhibitory concentration values of 0.11 to 1.2 nM. Infection of peripheral blood mononuclear cells could also be partly inhibited, although higher concentrations of EC2 proteins were required. Inhibition was largely coreceptor independent, as macrophage infections by virions pseudotyped with CXCR4 (X4)-tropic HIV-1 or vesicular stomatitis virus (VSV)-G glycoproteins were also inhibited, but was time dependent, since addition prior to or during, but not after, virus inoculation resulted in potent inhibition. Incubation with tetraspanins did not decrease CD4 or HIV-1 coreceptor expression but did block virion uptake. Colocalization of fluorescently labeled tetraspanin EC2 proteins and HIV-1 virions within, and with CD4 and CXCR4 at the cell surfaces of, macrophages could be detected, and internalized tetraspanin EC2 proteins were directed to vesicular compartments that contained internalized dextran and transferrin. Collectively, the data suggest that the mechanism of inhibition of HIV-1 infection by tetraspanins is at the step of virus entry, perhaps via interference with binding and/or the formation of CD4-coreceptor complexes within microdomains that are required for membrane fusion events.
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PMID:Recombinant extracellular domains of tetraspanin proteins are potent inhibitors of the infection of macrophages by human immunodeficiency virus type 1. 1677 36

The dichotomous effects of the protein kinase C (PKC) modulatory compounds 12-myristate 13-acetate (PMA), prostratin, and ingenol 3-angelate (I3A) on HIV-1 infection were investigated. PKC modulatory compounds were shown to be potent activators of cells latently infected with HIV-1 (I3A > prostratin). Conversely, PKC modulatory compounds inhibited infection of indicator cells (MAGI) with CXCR4-tropic HIV-1 (PMA > I3A > prostratin), and I3A also inhibited infection with CCR5-tropic virus (AD8-1). Pretreatment with the PKC inhibitors prior to treatment with either I3A or PMA resulted in increased infection, indicating inhibition is PKC mediated. Cell infections suggested that I3A rapidly inhibited the virus from infecting cells at an early point in infection. This observation was supported by the demonstration of inhibition at or before the synthesis of early reverse transcription products, and the inability of these compounds to block vesicular stomatitis virus (VSV) pseudotyped HIV-1 particles. As has already been shown with prostratin, treatment with I3A resulted in down-regulation of the CD4 receptor and CXCR4 coreceptor suggesting that this was a contributor to the infection inhibition. Intriguingly, 48 h pretreatment of unstimulated peripheral blood mononuclear cells (PBMC) prior to infection resulted in abrogation of virus production at concentrations where receptor/ coreceptor levels were not significantly reduced. This result hints at the possibility of inhibition by a PKC modulatory compound of an early pathway of viral entry in PBMC.
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PMID:HIV type 1 inhibition by protein kinase C modulatory compounds. 1698 10

Mouse cells do not support human immunodeficiency virus type 1 (HIV-1) replication because of host range barriers at steps including virus entry, transcription, RNA splicing, polyprotein processing, assembly, and release. The exact mechanisms for the suppression, however, are not completely understood. To elucidate further the barriers against HIV-1 replication in mouse cells, we analyzed the replication of the virus in lymphocytes from human CD4/CXCR4 transgenic mice. Although primary splenocytes and thymocytes allowed the entry and reverse transcription of HIV-1, the integration efficiency of the viral DNA was greatly reduced in these cells relative to human peripheral blood mononuclear cells, suggesting an additional block(s) before or at the point of host chromosome integration of the viral DNA. Preintegration processes were further analyzed using HIV-1 pseudotyped viruses. The reverse transcription step of HIV-1 pseudotyped with the envelope of murine leukemia virus or vesicular stomatitis virus glycoprotein was efficiently supported in both human and mouse cells, but nuclear import of the preintegration complex (PIC) of HIV-1 was blocked in mouse cells. We found that green fluorescent protein (GFP)-labeled HIV-1 integrase, which is known to be important in the nuclear localization of the PIC, could not be imported into the nucleus of mouse cells, in contrast to human cells. On the other hand, GFP-Vpr localized exclusively to the nuclei of both mouse and human cells. These observations suggest that, due to the dysfunction of integrase, the nuclear localization of PIC is suppressed in mouse cells.
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PMID:Nuclear import of the preintegration complex is blocked upon infection by human immunodeficiency virus type 1 in mouse cells. 1707 25

Host-derived anti-infective proteins represent an important source of sequences for designing antimicrobial peptides (AMPs). However such sequences are often long and comprise diverse amino acids with uncertain contribution to biological effects. Previously, we identified a simple highly cationic peptide derivative of human apolipoprotein E (apoEdp) that inhibited a range of microorganisms. Here, we have dissected the protein chemistry underlying this activity. We report that basic residues and peptide length of around 18 residues were required for activity; however, the Leu residues can be substituted by several other residues without loss of activity and, when substituted with Phe or Trp, resulted in peptides with increased potency. These apoEdp-derived AMPs (apoE-AMPs) showed no cytotoxicity and minimal haemolytic activity, and were active against HIV and Plasmodium via an extracellular target. CXCR4 and CCR5 strains of HIV were inhibited though an early stage in viral infection upstream of fusion, and a lack of inhibition of vesicular stomatitis virus G protein pseudotyped HIV-1 suggested the anti-HIV activity was relatively selective. Inhibition of Plasmodium invasion of hepatocytes was observed without a direct action on Plasmodium integrity or attachment to cells. The Trp-substituted apoE-AMP adhered to mammalian cells irreversibly, explaining its increased potency; NMR experiments confirmed that the aromatic peptides also showed stronger perturbation of membrane lipids (relative to apoEdp). Our data highlight the contribution of specific amino acids to the activity of apoEdp (and also potentially unrelated AMPs) and suggest that apoE-AMPs may be useful as lead agents for preventing the early stages of HIV and Plasmodium cellular entry.
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PMID:Apolipoprotein E-derived antimicrobial peptide analogues with altered membrane affinity and increased potency and breadth of activity. 1768 Oct 18


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