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)

The immunosuppressive effect of morphine in an HIV-1 transactivator of transcription (TAT)-transgenic mouse model was investigated in order to elucidate possible mechanisms of human immunodeficiency virus (HIV)-1 disease progression. The TAT72 transgene (1-72 amino acids) was placed under the control of SV40 viral promoter to provide systemic expression. Mice were treated daily for 5 days with morphine (50.0 mg/kg) or vehicle following alloantigen immunization. In TAT-transgenic mice, morphine modestly reduced mitogen-induced IL-2 production, which correlated with reduced percentages of CD4+ and CD8+ splenic lymphocytes. TAT-transgenic animals displayed reduced splenic natural killer (NK) and peritoneal cytotoxic T-lymphocyte (CTL) activities irrespective of morphine treatment. In addition, the effect of morphine on splenic NK and CTL activity was shown to be stereospecific as defined using (+)-morphine (50 mg/kg). Pretreatment of mice with the mu-selective opioid receptor antagonist beta-funaltrexamine (40.0 mg/kg) blocked morphine-induced modulation of splenic CTL activity. Since elevated corticosterone levels have previously been associated with immunosuppression following prolonged morphine exposure, serum corticosterone levels were assessed. Reduced serum corticosterone levels were found to be associated with morphine treatment in non-transgenic mice as well as vehicle- or morphine-treated mice. Collectively, the data suggest that the presence of TAT72 compromises splenic NK activity as well as peritoneal CTL activity and leads to a reduction in serum corticosterone levels. Also, morphine-mediated modulation of the immune system in non-transgenic mice is stereoselective and due in part to mu-opioid receptors.
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PMID:Immunologic characterization of TAT72-transgenic mice: effects of morphine on cell-mediated immunity. 770 68

We have reported the molecular cloning, expression, and characterization of a human cellular protein, TAP, which possesses a strong transcriptional activation domain and binds the human immunodeficiency virus type 1 Tat transactivator in vitro and in vivo (L. Yu, Z. Zhang, P.M. Loewenstein, K. Desai, Q. Tang, D. Mao, J.S. Symington, and M. Green, J. Virol. 69:3007-3016, 1995). Here we show that TAP binds the general transcription factor TFIIB. Furthermore, we delineate the binding domains of TAP, Tat, and TFIIB, as well as measure the strengths and specificity of these protein-protein interactions. TAP binds strongly to Tat, with a Kd of (approximately 2 to 5) x 10(-7) M. The Tat activation region contains a 17-amino-acid conserved core domain which is the single contact site for TAP. Single-amino-acid substitutions within the Tat core domain inactivate transactivation in vivo and in vitro and greatly reduce binding of Tat to TAP in vitro. TAP binds strongly to TFIIB, with about the same Kd as for Tat. The interaction between TAP and TFIIB requires a sequence near the carboxy terminus of TFIIB which is also required for binding the strong acidic activator VP16. The contact sites for Tat and TFIIB map within the TAP C-terminal region, which contains the TAP activation domain. These combined results are consistent with the hypothesis that TAP is a cellular coactivator that bridges the Tat transactivator to the general transcription machinery via TFIIB.
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PMID:In vitro interaction of the human immunodeficiency virus type 1 Tat transactivator and the general transcription factor TFIIB with the cellular protein TAP. 770 28

The viral transactivator proteins Rex and Rev are necessary for the expression of structural proteins of human T-cell leukemia virus type I and human immunodeficiency virus type 1, respectively. Although the interaction of Rex/Rev with a cellular cofactor(s) has been thought to be required for Rex/Rev action, there is no suitable system to search for the cofactor(s) in mammalian cells. We found that a Rex mutant, TAgRex, which contains a simian virus 40 nuclear localization signal in place of the N-terminal 19 amino acids of Rex, could dominantly inhibit wild-type Rex/Rev functions. The inhibition did not require either Rev response element/Rex response element binding or the oligomerization ability of the mutant, but it did require a region around amino acid 90 of the Rex protein, suggesting that TAgRex sequestered the cellular cofactor. Complementation with the eukaryotic translation initiation factor 5A (eIF-5A) in this system could restore the impaired Rex function. These results indicate that eIF-5A is the cofactor indispensable for Rex function. Additionally, by using a two-hybrid system, the homo-oligomer formation of Rex was found to be mediated by the region around amino acid 90 in addition to Tyr-64 and Trp-65 of Rex protein. Thus, eIF-5A may play a part in the formation of the Rex homo-oligomer.
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PMID:Effects of translation initiation factor eIF-5A on the functioning of human T-cell leukemia virus type I Rex and human immunodeficiency virus Rev inhibited trans dominantly by a Rex mutant deficient in RNA binding. 770 41

Infection by human immunodeficiency virus type 1 (HIV-1) causes acquired immunodeficiency syndrome (AIDS) after a long clinical latency. This disease is associated with a spectrum of cancers. Here we report that wild-type p53 is a potent suppressor of Tat, a major transactivator of HIV-1. Reciprocally, Tat inhibits the transcription of p53. Downregulation of p53 by upregulated tat may be important for the establishment of productive viral infection in a cell and also may be involved in the development of AIDS-related malignancies.
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PMID:Reciprocal modulations between p53 and Tat of human immunodeficiency virus type 1. 777 31

Functional cis-acting regulatory elements in the bovine immunodeficiency virus (BIV) long terminal repeat (LTR) were identified by deletion mapping and nuclear protein gel shift analysis using three BIV-infectible cell lines, Cf2Th, BLAC-20, and EREp. Deletion mapping studies indicated that putative NF-kappa B, GRE, AP-4, AP-1, CAAT, and ATF/CRE transcription factor elements positively contribute to LTR-directed gene expression in each cell line both in the presence and absence of the viral transactivator Tat. Sp1 and overlapping AP-3 and retroviral core enhancer elements had variable effects on LTR-directed gene expression depending on cell type and presence or absence of Tat. In addition, a sequence spanning the LTR U5 region and the untranslated viral leader was strongly repressive in all cell lines. Tat transactivated the LTR 25-fold over basal levels in a TAR-dependent manner in Cf2Th cells. In contrast, Tat transactivated the LTR only 2.5-fold over basal levels in EREp and BLAC-20 cells in a TAR-independent manner. Probes for putative NF-kappa B, GRE, Sp1, AP-4, AP-1, overlapping AP-3 and retroviral core enhancer, and juxtaposed CAAT and ATF-CRE elements specifically bound nuclear proteins from these three cell lines and HeLa cells, with the stoichiometry of binding being cell-type dependent. Probes for AP-4, AP-1, and juxtaposed CAAT and ATF/CRE elements exhibited greater protein binding with extracts from virally infected cells than with extracts from uninfected cells, suggesting that viral infection can modulate nuclear factor binding. The present studies indicate that several transcription factor elements in the BIV LTR have functional roles and that cell type can strongly determine the role they play in gene expression.
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PMID:cis-acting regulatory elements in the bovine immunodeficiency virus long terminal repeat. 777 92

Efficient replication of human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) requires the virus transactivator proteins known as Tat. In order to understand the molecular mechanisms involved in Tat transactivation, it is essential to identify the cellular target(s) of the Tat activation domain. Using an in vitro kinase assay, we previously identified a cellular protein kinase activity, Tat-associated kinase (TAK), that specifically binds to the activation domains of Tat proteins. Here it is demonstrated that TAK fulfills the genetic criteria established for a Tat cofactor. TAK binds in vitro to the activation domains of the Tat proteins of HIV-1 and HIV-2 and the distantly related lentivirus equine infectious anemia virus but not to mutant Tat proteins that contain nonfunctional activation domains. In addition, it is shown that TAK is sensitive to dichloro-1-beta-D-ribofuranosylbenzimidazole, a nucleoside analog that inhibits a limited number of kinases and is known to inhibit Tat transactivation in vivo and in vitro. We have further identified an in vitro substrate of TAK, the carboxyl-terminal domain of the large subunit of RNA polymerase II. Phosphorylation of the carboxyl-terminal domain has been proposed to trigger the transition from initiation to active elongation and also to influence later stages during elongation. Taken together, these results imply that TAK is a very promising candidate for a cellular factor that mediates Tat transactivation.
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PMID:Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor. 785 96

The activation of human immunodeficiency virus type 1 (HIV-1) expression in latently infected cells by exogenous agents is believed to be important in the progression of AIDS. Most factors that are known to activate HIV-1 gene expression increase the binding of NF-kappa B or NF-kappa B-like transcription factors to the HIV-1 core enhancer region. In this report, we demonstrate that retinoic acid (RA) treatment of promonocytic U937 cells stimulates expression from the simian immunodeficiency virus (SIVmac) long terminal repeat (LTR). Furthermore, RA and phorbol 12-myristate 13-acetate (PMA) synergistically stimulated both SIVmac and HIV-1 LTRs to levels of expression comparable to that achieved by the viral transactivator Tat. The cis-acting elements required for a response to RA and PMA cotreatment are located between nucleotides -50 and +1 of SIVmac and between nucleotides -83 and +80 of HIV-1. Thus, the synergistic stimulation induced by RA and PMA is NF-kappa B independent. Analysis of deletion mutants of the SIVmac LTR demonstrates that RA and PMA stimulation cooperates with NF-kappa B and Sp1. An SIVmac LTR-reporter gene construct [pLTR(-50/+466)CAT] lacking NF-kappa B and Sp1 binding sites was not activated by Tat in untreated cells but was activated in cells that were cotreated with RA and PMA. Furthermore, gel retardation assays demonstrated that RA treatment causes a change in the pattern of a cellular factor(s) which binds to the -50 through +1 region of the SIVmac LTR. These data suggest that RA induces a PMA-activatable cellular factor that cooperates with NF-kappa B, Sp1, or Tat to stimulate LTR-directed transcription.
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PMID:Synergistic activation of simian immunodeficiency virus and human immunodeficiency virus type 1 transcription by retinoic acid and phorbol ester through an NF-kappa B-independent mechanism. 808 95

The structure and functional peculiarities of a wide range of viral transcriptional transactivators have been considered. Analysis of literature data, concerning with the principles of functioning has made it possible to divide the viral transcriptional transactivators into three major groups: transcriptional transactivators of large DNA-containing viruses (Herpes simplex virus, Epstein-Barr virus, cytomegalovirus); transactivators of small DNA-containing viruses (papilloma viruses, papovaviruses, geminiviruses, parvoviruses) and viral coactivators. The latter group was identified in different DNA-containing viruses (Herpes simplex viruses, papilloma viruses, human T-leucosis virus, hepatitis B virus and adenoviruses). The conjecture about specific function of metal-binding motifs in activator domains of certain transcriptional activators is discussed. The functional features of human immunodeficiency virus TAT transactivator was considered separately by virtue of its RNA-binding activity.
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PMID:[Viral transcription trans-activators]. 815 78

The human immunodeficiency virus tat protein, a transactivator of viral and cellular genes, is suspected to be involved in the pathogenesis of acquired immunodeficiency syndrome-associated tumors. We report that transgenic mice carrying a recombinant DNA containing BK virus early region and the human immunodeficiency virus tat gene develop skin leiomyosarcomas, squamous cell papillomas and carcinomas, adenocarcinomas of skin adnexa, glands, and B-cell lymphomas. Although the incidence of hepatocellular carcinoma is low, most animals show a liver cell dysplasia of variable degree. These mice are also affected by skin lesions resembling the early stages of Kaposi's sarcoma. The transgene was detected intact in all the organs of transgenic mice, generally as multiple tandemly integrated copies. BK virus early region and tat were expressed in essentially all tissues and organs of BK virus/tat transgenic mice. This transgenic mouse model is representative of the systemic involvement of tat in human immunodeficiency virus natural infection and may be applied to investigate the role of tat in malignancies associated to acquired immunodeficiency syndrome, to study Kaposi's sarcoma pathogenesis and cell of origin, to characterize preneoplastic conditions established by tat in the skin and liver, and to assess in vivo the efficacy of antiangiogenic and anti-tat-specific drugs.
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PMID:Systemic expression of HIV-1 tat gene in transgenic mice induces endothelial proliferation and tumors of different histotypes. 822 99

Gene expression of human immunodeficiency virus (HIV) is modulated by both cellular transcription factors, which bind to cis-acting regulatory elements in the HIV-1 long terminal repeat (LTR) and the viral transactivator, tat. The enhancer element in the HIV-1 LTR which extends from -103 to -82 is critical for gene expression. This region contains two identical 10-bp direct repeats which serve as binding sites for members of the NF-kappa B family of transcription factors. However, several other cellular transcription factors, including a group of zinc finger DNA-binding proteins, also bind to NF-kappa B and related motifs. A member of this family of transcription factors, designated PRDII-BF1 or MBP-1, is a 300-kDa cellular protein which contains two widely separated zinc finger DNA binding domains. Each of these binding domains is capable of binding to NF-kappa B or related recognition motifs. Since no functional role for this protein has been demonstrated in the regulation of viral and cellular promoters, we began studies to determine whether PRDII-BF1 could modulate HIV-1 gene expression. DNase I footprinting of the HIV-1 LTR indicated that PRDII-BF1 bound to both NF-kappa B and TAR transactivation response DNA elements. Both in vitro translation and vaccinia virus expression of PRDII-BF1 cDNA resulted in the synthesis of the full-length 300-kDa PRDII-BF1 protein. Transfection experiments, using both eucaryotic expression vectors and antisense constructs, indicated that PRDII-BF1 activated HIV-1 gene expression in both the presence and absence of tat. These results are consistent with a role for PRDII-BF1 in activating HIV-1 gene expression.
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PMID:Transcription factor PRDII-BF1 activates human immunodeficiency virus type 1 gene expression. 828 30


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