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)

Human choriocarcinoma cells of the JAR line, with no demonstrable surface CD4 receptor were infected with human immunodeficiency virus type 1 (HIV-1), strain RF. Primer-directed enzymatic DNA amplification (polymerase chain reaction, PCR) detected the presence of viral DNA when the cultures were investigated at day 5 post-infection (p.i.). The absence of cytopathic changes attributable to virus replication suggested silent infection of these malignant trophoblastic cells. Neither reverse transcriptase (RT) activity nor HIV-specific antigens were found in the culture nutrient medium during JAR cell propagation. However, when the HIV-carrier JAR cells were continuously cultured and the cocultivation was initiated with CEM-SS lymphoblastoid cells after two subsequent passages, rescue of infectious virus was observed.
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PMID:In vitro productive infection of human malignant trophoblastic cell line JAR with human immunodeficiency virus type 1 (HIV-1). 168 80

One mechanism for expanding the cellular tropism of a virus is through the formation of phenotypically mixed particles or pseudotypes, a process commonly occurring during viral assembly in cells infected with two or more viruses. We report here that dual infection of cells with human immunodeficiency virus (HIV) and a murine amphotropic retrovirus leads to the production of HIV pseudotypes that have acquired the host range of the amphotropic retrovirus and are capable of infecting not only CD4- human cells but also mouse cells. The replication of the HIV pseudotypes in the various CD4- cells was determined by measuring the appearance of HIV antigens in the supernatants, by cocultivation of CD4+ CEM cells with the infected CD4- cells, and in some cases by assaying the culture supernatants directly for infectious virus. Of the cells tested, human foreskin fibroblasts were the best host cells, and by in situ cytohybridization, we were able to document that all cells in the culture were infected. In addition, the temporal appearance of HIV-specific proteins in the HIV pseudotype-infected fibroblasts was similar to that seen in CD4+ CEM cells. If the human fibroblasts were first infected with the amphotropic retrovirus, they demonstrated the property of superinfection exclusion and were resistant to subsequent infection by the HIV pseudotype. In other cell lines, including the human glioblastoma-derived cell line U373MG, HeLa cells, BALB/c mouse embryo cells, and SC-1 wild mouse cells, although the HIV pseudotype infection appeared to be less efficient, substantial amounts of HIV were nevertheless produced. These results indicate that the HIV (amphotropic retrovirus) pseudotypes may be useful for studying the molecular biology of HIV infections in a wide range of cells.
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PMID:Human immunodeficiency virus pseudotypes with expanded cellular and species tropism. 169 14

Chemotherapeutic agents which affect the integration, stability, or inducibility of the human immunodeficiency virus (HIV) provirus would have considerable value in treating acquired immunodeficiency syndrome. Two nucleoside analogs of cytosine, 5-azacytidine and 5-azadeoxycytidine, which seem to have such value because of their capabilities to affect both the stability and the methylation patterns of the nucleic acids into which they are incorporated, were tested for their ability to inhibit the replication of HIV type 1 (HIV-1) in human CEM T cells in vitro. 5-Azadeoxycytidine (1 microM) completely inhibited HIV replication in CEM cells, by the criteria of reduced viral antigen expression and decreased supernatant reverse transcriptase activity, with little toxicity for the treated cells. 5-azacytidine (1 microM) also inhibited HIV replication, but less effectively. When added 2 or more h after CEM cells were infected with HIV-1, both 5-azacytosine derivatives were less effective than they were when added at the time of infection. Even 2 h of exposure to 5-azadeoxycytidine was sufficient for inhibition of HIV replication. Although long exposure to either analog at concentrations of 1 microM would result in pronounced cellular cytotoxicity, the the fact that short exposures to the same dose of drug inhibit HIV replication but are not toxic for the cells implies that cellular toxicity itself is not an important mechanism of the antiviral action of the analogs.
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PMID:5-azacytidine and 5-azadeoxycytidine inhibit human immunodeficiency virus type 1 replication in vitro. 169 17

Three analogs of thymidine, D4T [2',3'-didehydro-2',3'-dideoxythymidine; 1-(2,3-dideoxy-beta-D-glyceropent-2-enofuranosyl)thymine], FddT (3'-fluoro-3'-deoxythymidine), and AZT (3'-azido-3'-deoxythymidine), were compared in biological tests designed to assess their potential utility as anti-human immunodeficiency virus (HIV) agents. The in vitro potencies of these compounds against HIV infection in CEM cells were measured, with FddT and AZT being more potent than D4T. The cytotoxicities of D4T, FddT, and AZT for CEM cells were comparable. The triphosphates of these three derivatives inhibited purified HIV reverse transcriptase, and their affinities for this polymerase were found to be 1 or 2 orders of magnitude greater than that for the normal substrate, dTTP. D4T was less toxic than FddT or AZT for cultured human and mouse bone marrow cells (granulocyte-macrophage CFU). The three compounds had similar toxicities for human progenitor erythrocyte burst-forming units. In a 30-day mouse toxicity study, AZT and FddT produced a similar spectrum of hematopoietic toxicities. These toxic effects occurred at much lower doses of FddT than of AZT. At the higher doses of FddT, a significant incidence of lethality occurred. By contrast, D4T was considerably less toxic than both AZT and FddT in this study. The dose-limiting toxicity of D4T in mice was hepatotoxicity. The very different phosphorylation patterns of D4T, its lower toxicity, and its comparable potency relative to FddT and AZT suggest that the potential of D4T as an anti-HIV agent should be further explored.
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PMID:Comparison of in vitro biological properties and mouse toxicities of three thymidine analogs active against human immunodeficiency virus. 169 57

Syncytium formation between HUT-78 cells persistently infected with human immunodeficiency virus type 1 (HIV-1) and uninfected CD4-bearing MOLT-4 or CEM cells results in a rapid destruction of the MOLT-4 or CEM cells. This syncytium formation is due to the interaction between the gp120 glycoprotein expressed by the persistently HIV-1-infected HUT-78 cells and the CD4 receptor present on MOLT-4 or CEM cells. A flow cytometric method has been applied to separate the infected (HUT-78) from the uninfected (MOLT-4, CEM) cell populations. This method is based on a modified DNA staining protocol which clearly shows the differences in DNA content between HUT-78 cells, on the one hand, and MOLT-4 or CEM cells, on the other hand. Using this flow cytometric method we have demonstrated that those compounds (i.e., sulfated polysaccharides, aurintricarboxylic acid) that interact with gp120 (of the HIV-infected cells) or CD4 (of the uninfected cells) suppress syncytium formation and concomitant destruction of the CD4+ cells.
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PMID:Flow cytometric method to monitor the destruction of CD4+ cells following their fusion with HIV-infected cells. 169 39

A new inhibitor of human immunodeficiency virus (HIV) has been isolated and purified to homogeneity from the seeds and fruits of the Momordica charantia. This compound, MAP 30 (Momordica Anti-HIV Protein), is a basic protein of about 30 kDa. It exhibits dose-dependent inhibition of cell-free HIV-1 infection and replication as measured by: (i) quantitative focal syncytium formation on CEM-ss monolayers; (ii) viral core protein p24 expression; and (iii) viral-associated reverse transcriptase (RT) activity in HIV-1 infected H9 cells. The doses required for 50% inhibition (ID50) in these assays were 0.83, 0.22 and 0.33 nM, respectively. No cytotoxic or cytostatic effects were found under the assay conditions. These data suggest that MAP 30 may be a useful therapeutic agent in the treatment of HIV-1 infections. The sequence of the N-terminal 44 amino acids of MAP 30 has been determined.
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PMID:MAP 30: a new inhibitor of HIV-1 infection and replication. 169 1

We investigated the nature of interaction of the malignantly transformed cell lines of trophoblast origin BeWo, JAR, and JEG-3 with three different human immunodeficiency virus type 1 (HIV-1) isolates (RF, 3B, and NDK). After inoculation with cell-free virus, the persistence of infection was determined for 1 month by monitoring the presence of viral DNA in the cells by the polymerase chain reaction (PCR). Furthermore, the infectious virus in the culture supernatant was assayed with CEM-SS cells, and attempts to rescue the virus by cocultivation with CEM-SS cells were made. Appraised on the basis of the relative amount of viral DNA and the frequency of positive cocultivation. JEG-3 was the most permissive and BeWo was the least permissive cell line. However, when the cells were transfected with two biologically active molecular clones of HIV-1, the BRU and NDK isolates, all three cell lines turned out to support the production of mature virus progeny to the same extent. The abundance of viral DNA sequences in the infected cells varied with the isolate, showing an overall decline from RF to NDK. The amount of viral DNA in the cells and its expression decreased during the period of observation; this decrease was mirrored in an erosion of the virus recovery rate at cocultivation from 71% recovery on day 8 to failure of isolation on day 32. None of the cell lines expressed detectable amounts of cell surface CD4 molecules when assayed by flow microfluorometry and direct radioimmunoassay. Northern (RNA) blot hybridization analysis of both the total RNA and the mRNA did not reveal any CD4-specific message: nonetheless, by using the PCR, sequences specifically related to the CD4 gene were uncovered. The data demonstrate that the trophoblast-derived cell lines are susceptible to infection with HIV and that they support transient viral replication in the initial phases of infection. However, the latent form of infection may persist over a period of several weeks.
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PMID:Human transformed trophoblast-derived cells lacking CD4 receptor exhibit restricted permissiveness for human immunodeficiency virus type 1. 170 98

A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. The lead compound, BI-RG-587, had a 50% inhibitory concentration of 84 nM against HIV-1 reverse transcriptase activity. This compound reduced plaque formation of HIV-1 in HeLa cells expressing the CD4 receptor by 50% at 15 nM. BI-RG-587 at comparable concentrations inhibited the production of p24 antigen following the acute infection of CEM T-lymphoblastoid cells or primary human monocyte-derived macrophages with HIV-1. No inhibitory effects against HIV-2 or against three picornaviruses were detected. Zidovudine (3'-azido-3'-deoxythymidine [AZT])-susceptible and AZT-resistant isolates of HIV-1 were equally susceptible to BI-RG-587. AZT and BI-RG-587 exhibited synergistic inhibition of HIV-1BRU at all concentrations examined.
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PMID:BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine. 170 76

Dimyristoylphosphatidylazidothymidine has been shown to inhibit human immunodeficiency virus (HIV) replication in CEM or U937 cells infected with the LAV-1 strain in vitro, but its metabolism and mechanism of antiretroviral activity have not been determined (Hostetler, K. Y., Stuhmiller, L. M., Lenting, H. B. M., van den Bosch, H., and Richman, D. D., J. Biol. Chem. (1990) 265, 6112-6117). We synthesized phosphatidylazidothymidine labeled with tritium in the 5'-position of dideoxyribose and incubated the phospholipid prodrug with CEM cells for 24 h. The radioactive products were analyzed by high pressure liquid chromatography and thin layer chromatography. Phosphatidylazidothymidine is deacylated by cellular phospholipases A to lysophosphatidylazidothymidine, which is subsequently hydrolyzed to glycero-3-phospho-5'-azidothymidine by lysophospholipases. Phosphodiesteratic cleavage of glycero-3-phospho-5'-azidothymidine occurs with formation of azidothymidine (AZT) or AZT-5'-monophosphate. Anabolic phosphorylation leads to the formation of AZT-diphosphate and AZT-triphosphate. To evaluate the possibility of direct inhibition of HIV reverse transcriptase by phosphatidyl-AZT, lysophosphatidyl-AZT or glycero-3-phospho-5'-AZT, we synthesized these compounds and found them to lack the ability to inhibit HIV recombinant reverse transcriptase in vitro. AZT-triphosphate was greater than 10,000 times more potent in inhibiting reverse transcriptase activity. Thus, phosphatidyl-AZT exerts its antiviral activity by metabolic conversion to AZT-triphosphate. Phospholipid prodrugs of this type may be useful in treating the macrophage reservoir of HIV infection.
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PMID:Phosphatidylazidothymidine. Mechanism of antiretroviral action in CEM cells. 171 Oct 37

Cell signaling events are known to affect human immunodeficiency virus type 1 (HIV-1) replication. Treatment of lymphoid CEM cells with the calcium channel blocker verapamil (25-75 microM) enhanced HIV-1 expression in acute, whole virus infection experiments, despite lowering intracellular calcium levels, ablating the acute rise in intracellular calcium normally seen with infection, and lengthening the doubling time of cell replication. Verapamil had no effect on cell surface CD4 expression. Transfection of CEM cells with plasmids containing the HIV-1 long terminal repeat linked to the chloramphenicol acetyltransferase reporter gene showed that verapamil enhanced expression of the HIV-1 long terminal repeat in a dose-dependent fashion. This effect was abolished by mutations in the binding sites for nuclear factor kappa-B. Electrophoretic mobility shift assays confirmed that verapamil induced nuclear factor kappa-B activity in CEM cells. Thus, verapamil, in high concentrations, can potentiate HIV-1 replication in lymphoid cells, and this effect may be mediated by induction of nuclear factor kappa-B.
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PMID:Effect of the calcium channel blocker verapamil on human immunodeficiency virus type 1 replication in lymphoid cells. 171 54


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