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)

1. The double-stranded RNA-dependent 2',5'-oligoadenylate (2-5A) synthetase/ribonuclease L (RNase L) system plays an essential role in the establishment of the antiviral state of a cell exposed to virus infection. 2. Until recently, the application of 2-5A derivatives to reinforce this system seemed to be limited mainly due to the low specificity of RNase L for viral RNA. 3. Two new strategies have been developed which yield a selective antiviral effect of 2-5As at least against human immunodeficiency virus-1 (HIV-1) infection: (i) an "intracellular immunization" approach using 2-5A synthetase cDNA linked to HIV trans-acting response element (TAR) and (ii) inhibition of retroviral reverse transcriptase activity by 2-5A analogues.
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PMID:(2'-5')Oligoadenylate and intracellular immunity against retrovirus infection. 137 26

An expression vector (pU3R-III/2-5AS) of human 2',5'-oligoadenylate (2-5A) synthetase was constructed in which a cDNA encoding an active form of the enzyme was located 3' to a 3'-long terminal repeat (LTR) of human immunodeficiency virus type 1 (HIV-1). The LTR-directed expression of this hybrid DNA could be activated in trans by the HIV tat gene product. This vector was used for transfection of HeLa-T4+ cells, which are permissive to HIV infection, as well as of normal HeLa cells. HIV replication after infection of the CD4-receptor-bearing HeLa-T4+ cells with HIV-1 was found to be strongly reduced when drug-selected cells cotransfected with pU3R-III/2-5AS and a hygromycin B resistance gene containing plasmid were used. In nontransfected cultures or after transfection with the selectable marker plasmid only, about 60% p17- and p24-positive cells were found 5 days after infection. However, after stable transfection with pU3R-III/2-5AS the number of positive cells was decreased to about 2%. The reverse transcriptase (RT) activity, as a measure for virus production, was markedly decreased in the culture fluids of pU3R-III/2-5AS transfected cells compared with the mock-transfected controls. In parallel experiments it was established that Tat-mediated trans-activation of HIV-1 LTR-directed 2-5A synthetase expression resulted in a great increase in both 2-5A synthetase mRNA level and activity as well as in cellular 2-5A content. Similar results were found in HeLa-T4+ cells and in HeLa cells (without CD4 receptor) cotransfected with pU3R-III/2-5AS and a tat gene containing plasmid or after introduction of purified Tat protein into the pU3R-III/2-5AS transfected cells by using a modified scrape loading procedure. These results indicate that HIV-trans-activated 2-5A synthetase can selectively inhibit HIV replication in vitro, and might be a promising gene therapeutical approach.
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PMID:Protection of HeLa-T4+ cells against human immunodeficiency virus (HIV) infection after stable transfection with HIV LTR-2',5'-oligoadenylate synthetase hybrid gene. 169 80

The following reviews the role of mRNA stability in the regulation of both viral and cellular gene expression in virus-infected cells. Indeed, several eukaryotic viruses, including the human immunodeficiency virus, HIV-1, regulate cellular protein synthesis via such control mechanisms. The following systems will be discussed: (i) the degradation of viral and cellular mRNAs in cells infected by herpes simplex virus (HSV) and advances made using the HSV virion host shutoff mutant; (ii) the degradation of viral and cellular mRNA and ribosomal RNA in cells infected by vaccinia virus and the possible role of the oligoadenylate synthetase-RNase L pathways; (iii) the turnover of RNAs in cells infected by encephalomyocarditis virus, reovirus, and La Crosse virus; and finally (iv) recent studies from our laboratory on the degradation of cellular mRNAs in cells infected by HIV-1.
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PMID:Regulation of viral and cellular RNA turnover in cells infected by eukaryotic viruses including HIV-1. 172 18

Translational effects of the RNA leader and Tat protein of human immunodeficiency virus type 1 (HIV-1) were investigated in rabbit reticulocyte lysate. Hybrid RNA species with natural or mutated HIV-1 leader fused to human interferon- gamma mRNA were produced in vitro from recombinant plasmids. HIV-1 leader RNA was found to inhibit translation through two mechanisms. A 3-fold trans-inhibition of translation was demonstrated by mixing hybrid HIV-1 leader RNA with indicator interferon mRNA. By comparison, HIV-1 leader caused a 50-fold cis-inhibition in lysate in which two trans-inhibitory factors, double-stranded RNA-dependent protein kinase and (2'-5')oligoadenylate synthetase, were suppressed. In contrast, purified HIV-1 Tat protein produced in Escherichia coli enhanced by 4-fold translation from HIV-1 leader-interferon mRNA but not from interferon mRNA lacking HIV sequences or from total poly(A)+ RNA. Translation of mRNA containing either a single base substitution in the loop of the "trans-acting responsive" sequence (TAR) or an alternative stem-loop in TAR was nevertheless stimulated by Tat. The enhancement of translation by Tat was largely due to relief of cis-inhibition, since the effect was found even in lysate in which double-stranded RNA-dependent protein kinase was inhibited with 2-aminopurine. These results suggest that translation is an important level of control in the replication cycle of HIV-1.
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PMID:Direct evidence for translational regulation by leader RNA and Tat protein of human immunodeficiency virus type 1. 212 Jul 1

Interferon alpha (IFN-alpha) induces significant antiretroviral activities that affect the ability of human immunodeficiency virus (HIV) to infect and replicate in its principal target cells, CD4+ T cells and macrophages. A major endogenous source of IFN-alpha during any infection is the macrophage. Thus, macrophages have the potential to produce both IFN-alpha and HIV. In this study, we examined the production of IFN-alpha and other cytokines by macrophage colony-stimulating factor (M-CSF)-treated cultured monocytes during HIV infection. Tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), IL-6, IFN-omega, or IFN-beta were not detected nor was the mRNA expressed in either uninfected or HIV-infected monocytes. However, both uninfected and HIV-infected monocytes produced high levels of each of these cytokines after treatment with synthetic double-stranded RNA [poly(I).poly(C)]. Uninfected monocytes also produced high levels of IFN-alpha after treatment with poly(I).poly(C), Newcastle disease virus, or herpes simplex virus. In marked contrast to the preceding observations, HIV-infected monocytes produced little or no IFN-alpha before or after treatment with any of these agents. The absence of detectable IFN-alpha activity and mRNA in poly(I).poly(C)-treated HIV-infected monocytes was coincident with high levels of 2',5' oligoadenylate synthetase and complete ablation of HIV gene expression. The antiviral activity induced by poly(I).poly(C) may be a direct effect of this synthetic double-stranded RNA or secondary to the low levels of IFN-beta and IFN-omega produced by infected cells. The markedly diminished capacity of HIV-infected monocytes to produce IFN-alpha may reflect a specific adaptive mechanism of virus to alter basic microbicidal functions of this cell. The inevitable result of this HIV-induced cytokine dysregulation is virus replication and persistence in mononuclear phagocytes.
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PMID:A selective defect of interferon alpha production in human immunodeficiency virus-infected monocytes. 198 24

Cellular mechanisms that control susceptibility to opportunistic infection in human immunodeficiency virus (HIV)-infected individuals remain poorly understood. HIV may induce certain cellular genes that restrict HIV replication and protect cells against other superinfecting viral pathogens. Indeed, HIV-infected monocytes resist infection by vesicular stomatitis virus (VSV). HIV-induced VSV interference in monocytes increases with time after HIV infection. Such interference was evident 6 h after HIV infection and reached maximal levels at 14 days. Monocytotropic but not T cell-tropic HIV strains elicited these effects, signaling a requirement for viral entry and/or replication. Viral interference was independent of interferon (IFN) and was unaffected by addition of neutralizing IFN-alpha and -beta antibodies. The well-described IFN-alpha-inducible antiviral pathways were examined to determine their relationship to the cellular mechanism(s) underlying VSV interference. HIV and IFN-alpha both induced the expression of 2-5A synthetase and Mx gene. In contrast, the guanylate-binding protein (GBP), 6-16, and 9-27 cellular genes were up-regulated by IFN-alpha but not HIV. MxA was detected in HIV-infected monocytes but not in uninfected monocytes. The association between Mx expression and resistance to VSV, coupled with previously described anti-VSV activities by human MxA, suggested that Mx may be an effector molecule for the HIV-induced anti-VSV activities. These results, taken together, suggest that HIV can induce antiviral cellular gene expression, independent of IFN.
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PMID:Regulation of interferon-alpha-inducible cellular genes in human immunodeficiency virus-infected monocytes. 750 41

2',5'-Oligoadenylate (2-5A) derivatives have been designed to act distal to the human immunodeficiency virus-1 (HIV-1)-induced blockade in the 2-5A synthetase/RNase L antiviral pathway. Stereochemical modification of individual internucleotide linkages of the 2-5A molecule was accomplished by phosphoramidite and phosphotriester chemical syntheses. Phosphorothioate/phosphodiester trimer and tetramer 2-5A derivatives revealed differences in the stereodynamics of activation of RNase L and inhibition of HIV-1 replication. The first and second internucleotide linkages are critical for activation of recombinant, human RNase L; A(Rp)ApA, A(Sp)ApA and ApA(Rp)A are agonists (IC50 = 2 x 10(-7), 2 x 10(-6) and 8 x 10(-6) M); ApA(Sp)A is an antagonist. The second and third internucleotide linkages are crucial for activation of murine RNase L; ApA(Rp)A, ApA(Rp)ApA, and ApApA(Rp)A are agonists (IC50 = 5 x 10(-7) M); ApA(Sp)A, ApA(Sp)ApA, and ApApA(Sp)A are antagonists. Inhibition of HIV-1-induced syncytia formation by the phosphorothioate/phosphodiester derivatives is specific for derivatives with substitution at the 2',3'-terminus. ApA(Rp)A, ApA(Sp)A, ApApA(Rp)A, and ApApA(Sp)A are potent inhibitors of HIV-1-induced syncytia formation (80-, 10-, 40-, and 15-fold more inhibitory, respectively, than solvent control). HIV-1 infection results in enhanced uptake and accumulation of ApA(Rp)A and ApA(Sp)A (7- and 10-fold, respectively). These stereochemically modified 2-5A derivatives are taken up preferentially by HIV-1-infected cells and show promise in anti-HIV-1 chemotherapy.
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PMID:Inhibition of HIV-1 replication and activation of RNase L by phosphorothioate/phosphodiester 2',5'-oligoadenylate derivatives. 789 Jul 27

The mismatched double-stranded RNA (dsRNA), poly(I).poly(C12U), also termed Ampligen, exhibits a strong antiviral and cytoprotective effect on cells (human T-lymphoblastoid CEM cells and human T-cell line H9) infected with the human immunodeficiency virus type 1 (HIV-1). Untreated H9 cells infected with HIV-1 start to release the virus 3 days post-infection, while in the presence of 40 micrograms/ml (80 micrograms/ml) of poly(I).poly(C12U) the onset of virus production and release is retarded and does not occur before day 5 (day 6). We demonstrate that poly(I).poly(C12U) markedly extends the duration of the transient increase of 2',5'-oligoadenylate (2-5A) synthetase mRNA level and activity preceding virus production after infection of cells with HIV-1. Treatment of HeLa cells with poly(I).poly(C12U) was found to cause a significant increase in total (activated plus latent) 2-5A synthetase activity; no evidence was obtained that the level of latent (nonactivated) 2-5A synthetase is changed in cells treated with dsRNA plus interferon (IFN). Poly(I).poly(C12U) is able to bind and to activate 2-5A synthetase(s) from HeLa cell extracts. Addition of poly(I).poly(C12U) to HeLa cell extracts results in production of longer 2-5A oligomers (> or = 3 adenylate residues), which are better activators of RNase L. Both free and immobilized poly(I).poly(C12U) also bind to the dsRNA-dependent protein kinase (p68 kinase), resulting in autophosphorylation of the enzyme. Activation of the kinase by the free RNA occurs within a limited concentration range (10(-7) to 10(-6) grams/ml). Addition of HIV-1 Tat protein does not affect binding and activation of p68 kinase to poly(I).poly(C12U)-cellulose but strongly reduces the binding of the kinase to immobilized TAR RNA of HIV-1. We conclude that poly(I).poly(C12U) may antagonize Tat-mediated down-regulation of dsRNA-dependent enzymes.
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PMID:Mode of action of the anti-AIDS compound poly(I).poly(C12U) (Ampligen): activator of 2',5'-oligoadenylate synthetase and double-stranded RNA-dependent kinase. 809 1

Human placenta contains a high level of 2',5'-oligoadenylate (2-5A) synthetase activity of the 100-kD form of the enzyme. About 20% of the placental 2-5A synthetase activity was found to be cytosolic, whereas the remaining 80% was released by 0.5 M KCl in the presence of detergent. Most of the enzyme activity was localized in trophoblast cells, which also contain a high level of 2-5A-dependent RNase L activity. The purified trophoblast 100-kD 2-5A synthetase was shown to be activated by human immunodeficiency virus type 1 (HIV-1) 5' RNA 1-311 and 1-707, which both contain the TAR and primer binding site (PBS) structured regions. These two HIV-1 RNAs activated human trophoblast 2-5A synthetase at the same level as poly(I).poly (C), a standard highly efficient activator of the enzyme, and at the same optimal concentration. On the contrary, HIV-1 RNA 311-618, a poorly structured region missing TAR and PBS, was shown to be a poor activator of the enzyme. The specific cellular location of the 2-5A synthetase and its efficient activation by HIV 5' RNA favors the idea that the trophoblast 2-5A system negatively controls HIV replication in trophoblasts.
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PMID:High levels of 2',5'-oligoadenylate synthetase and 2',5'-oligoadenylate-dependent endonuclease in human trophoblast. 845 85

The RNA stem-loop structure of the trans-activating region TAR sequence of human immunodeficiency virus-1 mRNA is the binding site for a number of host cell proteins. A virtually identical set of proteins from HeLa nuclear extracts was found to bind to the predicted RNA hairpin element of prion protein (PrP) mRNA, as demonstrated in UV cross-linking/RNase protection and Northwestern assays. We show that the cellular TAR loop-binding protein, p68, is among those proteins which associate with PrP RNA. Competition experiments with various TAR RNA mutants revealed that binding of partially purified p68 to PrP RNA stem-loop occurs sequence-specifically. The 100-kDa 2-5A synthetase which is involved in the cellular antiviral defense was able to bind to PrP mRNA stem-loop in Northwestern blots with cytosolic proteins from HeLa cells treated with interferon. However, the PrP RNA failed to activate this enzyme in vitro, in contrast to TAR RNA.
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PMID:Interaction of 68-kDa TAR RNA-binding protein and other cellular proteins with prion protein-RNA stem-loop. 922 82


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