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)

Phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II has been implicated as an important step in transcriptional regulation. Previously, we reported that a cellular CTD kinase, TAK, is targeted by the human immunodeficiency virus transactivator Tat. In the present study, we analyzed several other transactivators for the ability to interact with CTD kinases in vitro. The adenovirus E1A and herpes simplex virus VP16 proteins, but not other transactivators tested, were found to associate with a cellular kinase activity that hyperphosphorylates the CTD. The interaction is dependent upon a functional activation domain of E1A or VP16, suggesting that the interaction with a CTD kinase is relevant for the transactivation function of these proteins. The CTD kinase activities that interact with E1A and VP16 are related to each other but distinct from TAK. The Tat-, E1A- and VP16-associated CTD kinase activities detected in our assay also appear unrelated to MO15, the catalytic component of the CTD kinase activity of the general transcription factor TFIIH. Thus, this study has identified a novel interaction between viral transactivators and a cellular CTD kinase and suggests that at least two CTD kinases may mediate responses to viral transactivators.
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PMID:Viral transactivators specifically target distinct cellular protein kinases that phosphorylate the RNA polymerase II C-terminal domain. 860 64

The increased levels of tumor necrosis factor-alpha (TNF-alpha) seen in patients with acquired immune deficiency syndrome (AIDS) may contribute to the AIDS-related wasting syndrome. TNF also induces expression of human immunodeficiency virus (HIV) through activation of the transcription factor NF-kappa B, which binds to the viral long terminal repeat (LTR). Because TNF can decrease the antiretroviral activity of zidovudine (AZT) in vitro, pentoxifylline (PTX) may increase the efficacy of AZT. PTX decreases HIV replication in acutely infected cells and inhibits gene expression controlled by the HIV-1 LTR. The antiretroviral activity of PTX is associated with decreased binding of NF-kappa B to its recognition sequences. Therefore, PTX may inhibit HIV expression indirectly by diminishing TNF production and directly, by decreasing activity of NF-kappa B. PTX, and an inhibitor of the viral transactivator TAT, Ro24-7429, may inhibit HIV gene expression in a cooperative fashion. The first clinical study of PTX in AIDS patients was conducted by us through the AIDS Clinical Trial Group of the National Institutes of Health. AIDS patients on antiretroviral therapy received PTX 400 or 800 mg three times daily for 8 weeks. TNF assays included TNF mRNA levels in peripheral blood mononuclear cells (PBMCs) and inducible TNF protein levels in the supernatant of PBMCs cultured in the presence of 0.1 microgram/ml lipopolysaccharide (LPS). The median change in TNF mRNA was a 30% decrease. There was a median and significant 40% decrease in the production of inducible TNF protein. HIV load decreased in 10 patients and increased in four patients, but did not change in the group as a whole. Others have extended our initial observations in HIV-infected patients. In a placebo-controlled trial, TNF production by unstimulated PBMCs decreased by 52% in the PTX arm and increased by 7.2% in the placebo arm. In a study comparing AZT, PTX, or a combination of the two, viral load after treatment was ninefold above baseline in the AZT or PTX alone arm, compared to only twofold in the combination arm. In a quality of life trial, PTX was associated with improvement in depression, anger, and social and cognitive function: a placebo effect, however, was not ruled out. PTX 400 mg three times daily is safe and well tolerated. PTX decreases PBMC TNF expression in HIV-infected patients, measured as protein in culture supernatant or as mRNA, and may decrease viral replication. Further studies of HIV-infected persons are needed to ascertain the benefit of PTX as an adjunct either to inhibitors of reverse transcriptase (e.g., AZT) or of transcription (e.g., TAT inhibitor).
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PMID:Pentoxifylline for the treatment of HIV infection and its complications. 869 54

The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) contains two binding sites for the NF-kappa B/Rel family of transcription factors which are required for the transcriptional activation of viral genes by inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1. In the present study, we examined the effect of transdominant mutants of I kappa B alpha on the synergistic activation of the HIV-1 LTR by TNF-alpha and the HIV-1 transactivator, Tat, in Jurkat T cells. The synergistic induction of HIV-1 LTR-driven gene expression represented a 50- to 70-fold stimulation and required both an intact HIV-1 enhancer and Tat-TAR element interaction, since mutations in Tat protein (R52Q, R53Q) or in the bulge region of the TAR element that eliminated Tat binding to TAR were unable to stimulate LTR expression. Coexpression of I kappa B alpha inhibited Tat-TNF-alpha activation of HIV LTR in a dose-dependent manner. Transdominant forms of I kappa B alpha, mutated in critical serine or threonine residues required for inducer-mediated (S32A, S36A) and/or constitutive (S283A, T291A, T299A) phosphorylation of I kappa B alpha were tested for their capacity to block HIV-1 LTR transactivation. I kappa B alpha molecules mutated in the N-terminal sites were not degraded following inducer-mediated stimulation (t1/2, > 4 h) and were able to efficiently block HIV-1 LTR transactivation. Strikingly, the I kappa B alpha (S32A, S36A) transdominant mutant was at least five times as effective as wild-type I kappa B alpha in inhibiting synergistic induction of the HIV-1 LTR. This mutant also effectively inhibited HIV-1 multiplication in a single-cycle infection model in Cos-1 cells, as measured by Northern (RNA) blot analysis of viral mRNA species and viral protein production. These experiments suggest a strategy that may contribute to inhibition of HIV-1 gene expression by interfering with the NF-kappa B/Rel signaling pathway.
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PMID:Transdominant mutants of I kappa B alpha block Tat-tumor necrosis factor synergistic activation of human immunodeficiency virus type 1 gene expression and virus multiplication. 870 93

Unique transcriptional transactivation by the human immunodeficiency virus type 1 (HIV-1) Tat protein of long terminal repeat (LTR)-driven RNA expression, in the absence of the transactivator responsive element (TAR), was previously demonstrated in central nervous system (CNS)-derived astrocytic cell-lines, including U87MG. In the present study, RNase protection assays were utilized to reveal the molecular mechanism(s) underlying transactivation of the HIV-1-LTR in these cells. Short transcripts, which represent abortive HIV-1 transcription, could not be detected either in the absence or presence of Tat, and no differences in transcript levels were detected using 5' probes, as compared to 3' probes, in the experiments. Thus, the transactivational effects of Tat, in U87MG cells, were potentially based on the increase of transcriptional initiation, both in TAR-dependent and -independent states. Further, by using newly established stable cellular transformant, containing HIV-1-LTR-reporter gene constructs, TAR-independent transactivation was demonstrated to efficiently function primarily in transiently-transfected U87MG cells. U87MG cells, stably-transfected with the intact HIV-1 proviral genome, produced very low levels of virus after long-term culture, as previously reported in other astrocytic cells. These cells demonstrated profoundly restricted transcription of the HIV-1 genome, with no detectable levels of HIV-1-specific RNA by Northern blotting, indicating that the restriction of viral production in these cells is principally due to the low level of overall transcription from the 5' HIV-1-LTR. Transcription of HIV-1 RNA in this cell could not be significantly up-regulated by various stimulators, such as phorbol 12-myristate 13-acetate (PMA), tumor necrosis factor-alpha (TNF-alpha) and sodium butyrate. These data suggest that the restriction of HIV-1 transcription in these cells may be controlled by different mechanism(s) from those in lymphocytic or monocytic cells.
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PMID:Mechanisms of transcriptional transactivation and restriction of human immunodeficiency virus type I replication in an astrocytic glial cell. 871 Mar 70

Gene expression of human immunodeficiency virus (HIV-1) is greatly enhanced by a viral transactivator, the Tat protein, which interacts with R region sequences of the HIV-1 long terminal repeat (LTR). There is no direct evidence to indicate transcriptional activation of HIV-1 by Tat. Using an in vitro transcription system, we demonstrate that an established mouse cell line, which constitutively expresses Tat protein, selectively stimulates the steady state levels of the transcripts directed from the long terminal repeat (LTR) sequences of HIV-1. The gel binding retardation assays further demonstrate a stable activated complex, formed due to direct binding of Tat to DNA elements of the HIV-1 LTR. These data implicate transcription as the site of Tat action in trans-activation and could play an essential role in human immunodeficiency virus replication, similar to the nuclear trans-activators of other viruses.
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PMID:Tat mediates transcriptional activation of HIV-1 gene in vitro. 871 3

Precise regulation of major histocompatibility complex class II (MHC-II) gene expression plays a crucial role in the control of the immune response. A major breakthrough in the elucidation of the molecular mechanisms involved in MHC-II regulation has recently come from the study of patients that suffer from a primary immunodeficiency resulting from regulatory defects in MHC-II expression. A genetic complementation cloning approach has led to the isolation of CIITA and RFX5, two essential MHC-II gene transactivators. CIITA and RFX5 are mutated in these patients, and the wild-type genes are capable of correcting their defect in MHC-II expression. The identification of these regulatory factors has furthered our understanding of the molecular mechanisms that regulate MHC-II genes. CIITA was found to be a non-DNA binding transactivator that functions as a molecular switch controlling both constitutive and inducible MHC-II expression. The finding that RFX5 is a subunit of the nuclear RFX-complex has confirmed that a deficiency in the binding of this complex is indeed the molecular basis for MHC-II deficiency in the majority of patients. Furthermore, the study of RFX has demonstrated that MHC-II promoter activity is dependent on the binding of higher-order complexes that are formed by highly specific cooperative binding interactions between certain MHC-II promoter-binding proteins. Two of these proteins belong to families of which the other members, although capable of binding to the same DNA motifs, are probably not directly involved in the control of MHC-II expression. Finally, the facts that CIITA and RFX5 are both essential and highly specific for MHC-II genes make possible novel strategies designed to achieve immunomodulation via transcriptional intervention.
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PMID:Regulation of MHC class II genes: lessons from a disease. 871 17

Interactions between the Tax transactivator of human T-cell leukemia virus type 1 (HTLV-1) and a cell cycle regulatory protein have been examined. We report cooperative stimulation of human immunodeficiency virus type 1 gene expression by Tax and a regulator of cell cycle progression, the p21 cyclin-dependent kinase inhibitor (CKI). This cooperativity results from the effect of p21 on transcriptional coactivation by Tax-induced NF-kappaB. This effect was abrogated by a mutation in Tax which specifically eliminated NF-kappaB induction, was inhibitable by IkappaB-alpha, and was markedly reduced in human immunodeficiency virus reporter plasmids with mutant kappaB sites. These studies demonstrate that transcriptional activation by Tax is influenced by cell cycle regulatory proteins.
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PMID:A cooperative interaction of human T-cell leukemia virus type 1 Tax with the p21 cyclin-dependent kinase inhibitor activates the human immunodeficiency virus type 1 enhancer. 876 97

Expression of human immunodeficiency virus type 1 (HIV-1) provirus can be stimulated by herpes simplex virus type 1 (HSV-1) infection; the stimulation occurs at the level of transcriptional activation of the HIV long terminal repeat (LTR) and is mediated by both cellular and HSV-1-encoded transactivators. We have shown in this study that HSV-1 immediate-early gene ICP0 cooperates effectively with the HIV-1-encoded transactivator, Tat, in the stimulation of HIV-1 LTR-directed transcription. The cooperation between ICP0 and Tat is specific for the HIV-1 LTR and was not observed with other promoters (e.g., ICP0) that can be transactivated by ICP0 but not by Tat. Analyses of HIV-1 LTR deletion mutants have shown that ICP0 not only transactivates an HIV-1 LTR mutant that is unresponsive to NF-kappaB and Tat-mediated transactivation, such as the HIV-1 LTR with the enhancer deleted (-83 LTR) and TAR deleted (+20 to +81), but also restores responsiveness to Tat. ICP0 also showed cooperation with Gal4-Tat fusion protein-mediated transactivation of Gal4-HIV-1 LTR with TAR deleted. Enhancement of the transcriptional activation of ICP0 by Tat requires both the cysteine-rich and core domains of Tat and is inhibited by RO5-3335. ICP0 stimulates transcription of not only the HIV-1 LTR but also the TAR-defective HIV-1 provirus. We suggest that ICP0 can (i) recruit Tat to the vicinity of the HIV-1 promoter, thereby providing an alternative binding site for Tat, and (ii) substitute for the enhancer-binding proteins that are required for efficient Tat transactivation in T cells.
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PMID:Cooperation between herpes simplex virus type 1-encoded ICP0 and Tat to support transcription of human immunodeficiency virus type 1 long terminal repeat in vivo can occur in the absence of the TAR binding site. 879 37

Gene therapy approaches for human immunodeficiency virus type 1 (HIV-1) infections focus on the transfer of critical genetic elements into CD4+ T lymphocytes and CD34+ stem cells. Ideally, expression of the anti-HIV-1 gene constructs should be induced during early stages of infection to combat high turnover of the replicating virus. In this study, we investigated the activity of two promoters, HIV-1 long terminal repeat (HIV-1-LTR) and Rous sarcoma virus (RSV) LTR fused with the transactivation response element (TAR) from the HIV-1-LTR (ie RSV-TAR) in presence of Tat, the major HIV-1 transcriptional transactivator and an early gene product in HIV-1 infection. Comparative expression from both of these plasmids was analyzed by measuring expression of a reporter gene, chloramphenicol acetyltransferase (CAT), after transfection of the promoter-CAT constructs and a Tat-expressing plasmid into CEM T lymphocytic cells and peripheral blood mononuclear cells (PBMC). The HIV-1-LTR could be transactivated by Tat in both unstimulated and stimulated cells. Although the RSV-TAR had a relatively high basal level of expression, Tat transactivation of this chimeric promoter occurred only in unstimulated cells. These results suggest that the HIV-1-LTR may be a better promoter for therapeutic gene expression in anti-HIV-1 intracellular immunization approaches.
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PMID:Evaluation of relative promoter strengths of the HIV-1-LTR and a chimeric RSV-LTR in T lymphocytic cells and peripheral blood mononuclear cells: promoters for anti-HIV-1 gene therapies. 885 98

Clinical and experimental observations suggest that human herpesvirus-6 (HHV-6), a T-lymphotropic herpesvirus, may act as a cofactor in the acquired immunodeficiency syndrome (AIDS). Moreover, a possible role of HHV-6 in the increased incidence and severity of cervical carcinoma in human immunodeficiency virus (HIV)-infected women was suggested by the recent observation that HHV-6 can infect cervical carcinoma cells, accelerating their tumorigenicity in vivo. Therefore, the ability of four HHV-6 genomic clones derived from HHV-6 to transactivate the long terminal repeat (LTR) of HIV-1 in two cervical carcinoma cell lines and in a T-lymphoid cell line was tested. Two HHV-6 clones, pZVH-14 and pZVB-70, which were previously shown to increase the expression of human papillomavirus (HPV)-transforming genes, were, per se, weak transactivators of the HIV-1 LTR. However, an increased effect occurred when these clones were combined with the HIV-1 transactivator TAT-1. No such effect was seen with two other HHV-6 clones used as controls. Analysis with HIV-1 LTR deletion mutants indicated that this enhancing effect requires the presence of elements contained in both the enhancer region and the TAT activation region (TAR) of HIV-1. This data may have implications for the potential role of HHV-6 in AIDS and AIDS-related cervical carcinoma.
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PMID:Enhancement of TAT-induced transactivation of the HIV-1 LTR by two genomic fragments of HHV-6. 889 36


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