Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Tat protein of human immunodeficiency virus type 1 (HIV-1) is essential for productive infection and is a potential target for antiviral therapy. Tat, a potent activator of HIV-1 gene expression, serves to greatly increase the rate of transcription directed by the viral promoter. This induction, which seems to be an important component in the progression of acquired immune deficiency syndrome (AIDS), may be due to increased transcriptional initiation, increased transcriptional elongation, or a combination of these processes. Much attention has been focused on the interaction of Tat with a specific RNA target termed TAR (transactivation responsive) which is present in the leader sequence of all HIV-1 mRNAs. This interaction is believed to be an important component of the mechanism of transactivation. In this report we demonstrate that in certain CNS-derived cells Tat is capable of activating HIV-1 through a TAR-independent pathway. A Tat-responsive element is found upstream within the viral promoter that in glial-derived cell lines allows transactivation in the absence of TAR. Deletion mapping and hybrid promoter constructs demonstrate that the newly identified Tat-responsive element corresponds to a sequence within the viral long terminal repeat (LTR) previously identified as the HIV-1 enhancer, or NF-kappa B domain. DNA band-shift analysis reveals NF-kappa B binding activity in glial cells that differs from that present in T lymphoid cells. Further, we observe that TAR-deleted mutants of HIV-1 demonstrate normal late gene expression in glial cells as evidenced by syncytia formation and production of viral p24 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation. 150 23

The TAR sequence of the 5' leader of HIV-1 long terminal repeat-directed mRNA was found to be able to bind to and to activate double-stranded RNA-dependent (2'-5')A synthetase. Binding of TAR to the purified synthetase in vitro was abolished by addition of HIV-1 Tat protein, which binds to this sequence with a high affinity. Inhibition of TAR-mediated activation of (2'-5')A synthetase by Tat was prevented in the presence of the Zn2+ and Cd2+ chelators o-phenanthroline and penicillamine, which did not impair TAR-synthetase interaction. Transient expression assays of bacterial chloramphenicol acetyltransferase (CAT) gene in HeLa cells revealed that the levels of both CAT mRNA and CAT protein decreased after treatment of the cells with interferon, if CAT gene was linked to HIV-1 TAR segment. Cotransfection of the cells with a tat sequence containing plasmid rendered CAT gene expression insensible to the action of interferon.
AIDS Res Hum Retroviruses 1990 May
PMID:Binding of Tat protein to TAR region of human immunodeficiency virus type 1 blocks TAR-mediated activation of (2'-5')oligoadenylate synthetase. 169 53

Human immunodeficiency virus type 2 (HIV-2) gene expression is downmodulated by sequence elements downstream of the transcriptional initiation site, corresponding to the U5 region of the long terminal repeat (LTR) and further downstream. This repression appeared to be related more to the length of the sequence intervening the transcriptional initiation site and the coding region than to a particular sequence content. The repressive effect of the downstream segment was not affected by HIV-2 and HIV-1 TAT or by the cytomegalovirus transactivator IE-2 gene. Nor was it affected by T-cell activation signals or by such cytokines as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interferon-gamma (IFN gamma), and interferon-alpha (IFN alpha). In contrast to HIV-1, HIV-2 LTR-directed gene expression was not modulated by TNF-alpha. A specific sequence element, located downstream of the TAR element in the R region, seemed to participate in modulation of gene expression. This element interacted with a nuclear protein with a mobility of about 26 kD. The repressive effect of the downstream sequence was to a certain extent cell type dependent, suggesting the involvement of cell type-specific factors. It was more effective in human lymphocytic CEM cells than in Jurkat cells. This may be relevant to the HIV-2 cell tropism (replication), latency, and virulence.
AIDS Res Hum Retroviruses 1991 Dec
PMID:Human immunodeficiency virus type 2 (HIV-2) gene expression: downmodulation by sequence elements downstream of the transcriptional initiation site. 181 41

Toward gene therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections in AIDS, Moloney murine leukemia virus-derived retroviral vectors were engineered to allow constitutive and tat-inducible expression of an HIV-1 5' leader sequence-specific ribozyme (Rz1). These vectors were used to infect the human CD4+ lymphocyte-derived MT4 cell line. The stable MT4 transformants expressing an HIV-1 RNA-specific ribozyme, under the control of the herpes simplex virus thymidine kinase (tk) promoter, were found to be somewhat resistant to HIV-1 infection as virus production was delayed. In cells allowing ribozyme expression under control of the simian virus 40 or cytomegalovirus promoter, the rate of HIV-1 multiplication was slightly decreased, and virus production was delayed by about 14 days. The highest level of resistance to HIV-1 infection was observed in MT4 cells transformed with a vector containing a fusion tk-TAR (trans activation-responsive) promoter to allow ribozyme expression in a constitutive and tat-inducible manner; no HIV-1 production was observed 22 days after infection of these cells. These results indicate that retroviral vectors expressing HIV-1 RNA-specific ribozymes can be used to confer resistance to HIV-1 infection.
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PMID:Resistance to human immunodeficiency virus type 1 (HIV-1) infection in human CD4+ lymphocyte-derived cell lines conferred by using retroviral vectors expressing an HIV-1 RNA-specific ribozyme. 189 2

The course of drug development for the treatment of HIV-1 infection and AIDS is being revolutionized by high-resolution structures of essential viral proteins. We survey the impact on drug design of the recently elucidated structural knowledge of two essential enzymes, reverse transcriptase and protease, and three new targets, the viral integrase and the gene regulatory protein-RNA interactions, Tat-TAR and Rev-RRE.
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PMID:Progress in anti-HIV structure-based drug design. 754 68

The TAt protein of the human immunodeficiency virus type 1 (HIV-1) activates the expression of viral mRNA through a cis-acting element in the LTR termed TAR. TAR RNA forms a stable stem-loop structure. Mutagenesis studies indicate that the stem structure, the primary sequence of the loop, and three unpaired bases in the stem (bulge) are important for Tat activation. Using the in vitro-transcribed TAR RNA as a probe, we have cloned a gene (TARBP-b) that encodes a TAR-binding protein from a cDNA expression library derived from Hut-78 cells. Expression of the 1.4-kb TARBP-b mRNA was observed in all mammalian cell lines tested. TARBP-b binds specifically to the bulge region of TAR RNA and trans-activates the HIV-1 long terminal repeat in the presence of ptat and prev expression plasmids. These results suggest that TARBP-b contributes to tat-mediated trans-activation.
AIDS Res Hum Retroviruses 1995 Jun
PMID:Molecular cloning and characterization of a TAR-binding nuclear factor from T cells. 757 25

The tat gene product (Tat) of HIV-1 is an early regulatory protein necessary for viral gene expression and replication. Tat may also play a role as an extracellular protein in both HIV-1 replication and AIDS-associated disorders such as Kaposi's sarcoma. Thus, Tat represents a good target for gene therapy against AIDS. Here we show that when vectors expressing antisense tat RNA are transiently transfected into CD4+ cells, they block about 70% of HIV-1 replication and inhibit the rescue of Tat-defective HIV-1 proviruses by inhibition of Tat protein expression and consequent lack of transcriptional activation of the HIV-promoter. However, antisense tat vectors cannot block the activity of extracellular Tat protein. Another tat inhibitory construct (poly-Tat-activation response; TAR) previously suggested to inhibit HIV-1 transactivation by sequestering the Tat protein, inhibited the activity of extracellular Tat, but like antisense tat RNA did not completely block viral gene expression and replication. These results suggested that one mode of inhibition is not sufficient to block Tat function. However, when the antisense tat and the poly-TAR constructs were combined HIV-1 gene expression was completely blocked (94-98%), suggesting that a combination of inhibitory genes blocking Tat by sequential steps may be a better approach for AIDS gene therapy.
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PMID:Block of HIV-1 infection by a combination of antisense tat RNA and TAR decoys: a strategy for control of HIV-1. 758 83

Antitat is an autoregulated gene expressing an inhibitory RNA with dual function: it sequesters the Tat protein by polymeric-TAR and blocks the translation of the Tat messenger RNA by antisense-Tat. Using human T cell lines and peripheral blood lymphocytes as the in vitro target, we have previously shown that antitat is an effective long-term suppressor of HIV-1, including 'field' isolates. To assess the efficacy of this inhibitory gene better in the setting of an infected individual with late-stage AIDS, we examined its antiviral activity in an in vivo established infection. Peripheral blood mononuclear cells isolated from AIDS patients were transduced with replication defective retroviral vectors carrying the antitat gene. In the absence of cell selection, the antitat gene blocked virus replication and allowed infected CD4+ T cells to expand in culture. These results suggest that antitat gene therapy may be beneficial to block HIV-1 replication and reconstitute the immune system of late-phase AIDS patients. We introduced a new parameter, CRF, which defines the effectiveness of the ex vivo gene therapy treatment of AIDS patients. Antitat treatment was efficient in cells of all patients regardless of viral quasispecies, however, it was most potent in severely immunocompromised individuals.
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PMID:Antitat gene therapy: a candidate for late-stage AIDS patients. 761 53

Productive infection with HIV-1, the virus responsible for AIDS, requires the involvement of host cell factors for completion of the replicative cycle, but the identification of these factors and elucidation of their specific functions has been difficult. A human cDNA, TRBP, was recently cloned and characterized as a positive regulator of gene expression that binds to the TAR region of the HIV-1 genome. Here we demonstrate that this factor is encoded by a gene, TARBP2, that maps to human chromosome 12 and mouse chromosome 15, and we also identify and map one human pseudogene (TARBP2P) and two mouse TRBP-related sequences (Tarbp2-rs1, Tarbp2-rs2). The map location of the expressed gene identifies it as a candidate for the previously identified factor encoded on human chromosome 12 that has been shown to be important for expression of HIV-1 genes. Western blotting indicates that despite high sequence conservation in human and mouse, the TARBP2 protein differs in apparent size in primate and rodent cells.
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PMID:Genetic mapping in human and mouse of the locus encoding TRBP, a protein that binds the TAR region of the human immunodeficiency virus (HIV-1). 777 57

The Human Immunodeficiency Virus type 1 (HIV-1) Tat protein is a potent activator of transcription directed by the long terminal repeat (LTR), an essential step in the life-cycle of HIV-1. While interaction of Tat with an RNA element encoded by downstream LTR sequences (termed TAR) is commonly considered essential to activation, numerous recent reports have implicated upstream transcription elements within the LTR as participants in mediating this activation. We have recently demonstrated that Tat activation occurs independent of the TAR element in certain cells derived from the central nervous system (CNS), and that this activation is mediated by the kappa B domain of the LTR. Further, CNS-derived cells were found to contain kappa B-binding activity capable of both interacting with Tat and activating LTR transcription in vitro. The present study demonstrates that the kappa B-binding transcription factor derived from CNS cells consists of a component indistinguishable from prototypical Nuclear Factor-kappa B (NF-kappa B) (in size, mobility on native gel, kinetics of activation and cognate binding sequence) as well as a supershifting component that is dissociable under certain conditions. The supershifting activity is found to stabilize binding of the presumed NF-kappa B to DNA. Further, only the form of NF-kappa B which is associated with this supershifting activity is capable of binding Tat. We hypothesize a model in which Tat utilizes this interaction to activate HIV-1 through the NF-kappa B domain of the LTR in circumstances where TAR is absent. This model has implications with respect to the ability of Tat to alter cellular gene expression and perhaps contribute to the array of problems seen in HIV-1 infection such as altered immune status, CNS toxicity, and the formation of tumors.
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PMID:A CNS-enriched factor that binds to NF-kappa B and is required for interaction with HIV-1 tat. 783 36


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