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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular transcription factors play critical roles in regulating human immunodeficiency virus (HIV) gene transcription, although the precise mechanism(s) defining their roles are not well established. Primarily it has been suggested that sequence-specific interaction of trans-activating proteins with cis-acting DNA elements plays a crucial role in regulating the target genes. The negative regulatory element (NRE) of HIV-1 long terminal repeat (LTR) is one such defined region that has been reported to down-regulate LTR-directed HIV gene expression. Information regarding the role of this region in the regulation of HIV expression is lacking. Here we describe an attempt to further characterize the role of NRE cis-elements and define any sequence-specific interaction with cellular factors. Using gel mobility shift DNA-binding and Southwestern blot assays, we have mapped a distinct region of NRE (-290 to -260, a 30-base pair (bp) domain of NRE-A) sequences of HIV-1 LTR, which recognizes a specific DNA-binding protein from HeLa cell nuclear extracts. This factor is a 38-kDa polypeptide which can be affinity-purified to near homogeneity by this 30-bp specific oligonucleotide in affinity chromatography. The cellular factor from HeLa cell nuclear extract exhibits specific interaction only with the 30-bp NRE-A domain of HIV-1 LTR and acts as a strong transcriptional repressor/inhibitor molecule in the DNA-protein gel binding, as well as in vitro transcriptional studies with the nuclear extracts from cells with productive HIV-1 infection. To our knowledge, this is the first report of a factor recognizing a distinct segment within NRE that has been shown to exert an inhibitory effect on transcriptionally active DNA-protein "pre-initiation" complex formation, suggesting a possible role in HIV-1 gene regulation.
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PMID:Characterization and purification of a novel transcriptional repressor from HeLa cell nuclear extracts recognizing the negative regulatory element region of human immunodeficiency virus-1 long terminal repeat. 145 99

This review describes the potential role of oxidative stress as a cofactor of disease progression from asymptomatic human immunodeficiency virus (HIV) infection to the acquired immunodeficiency syndrome (AIDS). Oxidative stress is a known activator of HIV replication in vitro through the activation of a factor that binds to a DNA-binding protein, NF-kappa B, which in turn stimulates HIV gene expression by acting on the promoter region of the viral long terminal repeat. Tumor necrosis factor alpha (TNF-alpha), an essential cytokine produced by activated macrophages, is also involved in the activation of HIV infection through similar mechanisms. TNF-mediated cytotoxicity of cells exposed to this substance is related to the generation of intracellular hydroxyl radicals. An indirect argument in favor of the role of oxidative stress in HIV-associated disease progression is the consumption of glutathione (GSH), a major intracellular antioxidant, during HIV infection and progression. GSH is known to play a major role in regulation of T cell immune functions. Oxidative stress may also play an important role in the genesis of cellular DNA damage and, in this context, may be related to HIV-associated malignancies and disease progression. Finally, the role of antioxidants as components of therapeutic strategies to combat HIV disease progression is discussed.
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PMID:The role of oxidative stress in disease progression in individuals infected by the human immunodeficiency virus. 164 Jan 66

We have cloned and characterized a mitogen-inducible gene isolated from human T cells that predicts a protein of 968 amino acids. The amino-terminal domain has regions homologous to the oncogene rel and to the developmentally important gene dorsal of Drosophila. The carboxy-terminal domain contains repeat structures found in a variety of proteins that are involved in cell-cycle control of yeast and in tissue differentiation in Drosophila and Ceanorhabditis elegans, as well as in the putative human oncogene bcl-3 and in the ankyrin protein. A truncated form of the product of this gene translated in vitro is a DNA-binding protein which interacts specifically with the kappa B binding site found in many inducible genes, including the enhancer in human immunodeficiency virus. This gene is yet another in a growing list of important regulatory molecules whose expression is transcriptionally induced upon cellular activation.
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PMID:Cloning of a mitogen-inducible gene encoding a kappa B DNA-binding protein with homology to the rel oncogene and to cell-cycle motifs. 223 62

A defect in a trans-regulatory factor which controls major histocompatibility complex class II gene expression is responsible for an inherited form of immunodeficiency with a lack of expression of human leukocyte antigen (HLA) class II antigens. We have recently described and cloned an HLA class II promoter DNA-binding protein, RF-X, present in normal B cells and absent in these class II-deficient regulatory mutants. Here we report that these in vitro results correlate with a specific change in the chromatin structure of the class II promoter: two prominent DNase I-hypersensitive sites were identified in the promoter of the HLA-DRA gene in normal B lymphocytes and found to be absent in the class II-deficient mutant cells. The same two prominent DNase I-hypersensitive sites were observed in normal fibroblastic cells induced by gamma interferon to express class II genes. Interestingly, they were also observed in the uninduced class II-negative fibroblastic cells, which have also been shown to have a normal RF-X binding pattern. We conclude that the two DNase I-hypersensitive sites in the HLA-DRA promoter reflect features in chromatin structure which correlate with the binding of the trans-acting factor RF-X and which are necessary but not sufficient for the expression of class II genes.
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PMID:Inherited immunodeficiency with a defect in a major histocompatibility complex class II promoter-binding protein differs in the chromatin structure of the HLA-DRA gene. 246 88

The polymerase chain reaction (PCR) procedure has many potential applications in mass screening. We describe here a general assay for colorimetric detection of amplified DNA. The target DNA is first amplified by PCR, and then a second set of oligonucleotides, nested between the first two, is incorporated by three or more PCR cycles. These oligonucleotides bear ligands: for example, one can be biotinylated and the other can contain a site for a double-stranded DNA-binding protein. After linkage to an immobilized affinity reagent (such as a cloned DNA-binding protein, which we describe here) and labeling with a second affinity reagent (for example, avidin) linked to horseradish peroxidase, reaction with a chromogenic substrate allows detection of the amplified DNA. This amplified DNA assay (ADA) is rapid, is readily applicable to mass screening, and uses routine equipment. We show here that it can be used to detect human immunodeficiency virus sequences specifically against a background of human DNA.
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PMID:Colorimetric detection of specific DNA segments amplified by polymerase chain reactions. 264 2

We used site-directed mutagenesis to delineate sequences within the human immunodeficiency virus type I (HIV-I) long terminal repeat (LTR) required for trans-activation by the viral tat gene product. We demonstrated that sequences 3' to LTR position +44 are dispensable for trans-activation but that almost all of the mutations tested located between positions -17 and +44 greatly reduced trans-activation at both the transcriptional and posttranscriptional levels. However, displacement of the HIV-I LTR trans-activation-responsive region (TAR) 3' by insertion of up to 32 base pairs between the LTR TATA box and cap site had little effect on trans-activation. An analysis of the DNase I hypersensitivity profile of the HIV-I LTR in transfected cultures suggested the presence of at least two DNase I-hypersensitive sites, including one which extends into the viral TAR element; however, neither of these sites appeared to be significantly affected by tat coexpression. These results allow more precise delineation of the sequences important for TAR function and suggest that the TAR may be recognized by a host-specific DNA-binding protein rather than by the tat protein directly.
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PMID:Mutational analysis of the trans-activation-responsive region of the human immunodeficiency virus type I long terminal repeat. 282 63

The expression of human immunodeficiency virus (HIV) after T cell activation is regulated by NF-kappa B, an inducible DNA-binding protein that stimulates transcription. Proteins encoded by a variety of DNA viruses are also able to activate expression from the HIV enhancer. To determine how this activation occurs, specific genes from herpes simplex virus type 1 and adenovirus that activate HIV in T lymphoma cells have been identified. The cis-acting regulatory sequences in the HIV enhancer that mediate their effect have also been characterized. The relevant genes are those for ICP0-an immediate-early product of herpes simplex virus type 1-and the form of E1A encoded by the 13S messenger RNA of adenovirus. Activation of HIV by adenovirus E1A was found to depend on the TATA box, whereas herpesvirus ICP0 did not work through a single defined cis-acting element. These findings suggest multiple pathways that can be used to bypass normal cellular activation of HIV, and they raise the possibility that infection by herpes simplex virus or adenovirus may directly contribute to the activation of HIV in acquired immunodeficiency syndrome by mechanisms independent of antigenic stimulation in T cells.
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PMID:Alternative mechanisms for activation of human immunodeficiency virus enhancer in T cells. 283 Jun 75

The transition from persistent to lytic infection by the human immunodeficiency virus, HIV, is marked by a burst of viral replication and gene expression that occurs when infected cells are stimulated by physiological inducers or tumor promoters like 12-O-tetradecanoyl phorbol acetate (TPA). We report here that the HIV enhancer is activated specifically by TPA in several non-lymphoid cell types, and that this transcriptional regulation can be reproduced in a cell-free system. In vitro transcription experiments revealed a 6-fold activation of the HIV promoter in nuclear extracts prepared from TPA-induced HeLa tk- cells, whereas a control (human alpha-globin) promoter was transcribed with equal efficiency in either induced or uninduced cell extracts. A corresponding increase in the activity of a cellular DNA-binding protein that interacts with the HIV enhancer was detected in TPA-treated cells with DNase I footprint experiments. This increase occurred in the absence of de novo protein synthesis, suggesting a post-transcriptional activation mechanism. Analysis of HIV deletion mutants suggests that the enhancer is the target for the TPA effect both in vitro and in vivo. The cell-free system described here should facilitate studies on the mechanism of phorbol ester induction of gene-specific transcription factors.
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PMID:In vitro activation of the HIV-1 enhancer in extracts from cells treated with a phorbol ester tumor promoter. 344 2

Papillomaviruses are the causative agents of benign and malignant epithelial tumors of the skin and mucosa. They encode a DNA-binding protein, E2, that regulates viral transcription and replication, making it an important therapeutic target. By deleting the amino-terminal trans-activation domain of human papillomavirus type 16 (HPV-16) E2 while retaining its carboxy-terminal DNA binding and dimerization domain, an E2 repressor (E2R) that efficiently inhibits transcriptional activation by full-length HPV E2 was generated. To deliver this repressor protein into animal cells, we have utilized the human immunodeficiency virus type 1 (HIV-1) Tat protein which itself is taken up efficiently into intact cells. Chimeras of E2R and the cellular uptake domain of Tat specifically inhibited E2-dependent reporter gene expression in COS-7 cells. Treatment of cervical intraepithelial neoplasia cells having episomally replicating HPV-31 DNA with this Tat-E2R protein led to a dose-dependent loss of HPV DNA copies and inhibition of cell growth. Tat-mediated delivery can be a valuable tool for assessing protein function and may allow the development of novel therapeutic proteins having intracellular targets.
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PMID:Specific inhibition of a human papillomavirus E2 trans-activator by intracellular delivery of its repressor. 794 33

The p53 tumor suppressor gene product, a sequence-specific DNA-binding protein, has been shown to act as a transcriptional activator and repressor both in vitro and in vivo. Consistent with its role in regulating transcription are recent observations that the N-terminal acidic domain of p53 binds directly to the TATA box-binding protein subunit of the general transcription factor, TF IID. It is now demonstrated that wild-type p53 (wt-p53) inhibits human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-directed chloramphenicol acetyltransferase activity in a cotransfection assay system. Importantly, this effect of wt-p53 on the HIV-1 LTR was also demonstrated by in vitro transcription assays. In addition, the Sp1 sites and the TATA box of the HIV-1 LTR are demonstrated to be the primary sites involved with p53-induced effects on this viral promoter. The upstream elements of the HIV-1 LTR, including the nuclear factor kappa B (NF-kappa B) binding sites, decrease the p53-induced inhibitory effects on viral transcription. In the presence of the HIV-1 TAR sequence and Tat protein, the HIV-1 LTR also becomes less sensitive to wt-p53-induced inhibition. By using a retroviral vector delivery system, mutant forms of p53 genes were expressed in two HIV-1 latently infected cell lines, ACH-2 and U1. In the ACH-2 cell line, which is now demonstrated to contain an endogenous mutant form of p53 (amino acid 248, Arg to Gln), additional mutant p53 proteins did not alter HIV-1 replication. In U1 cells, which completely lack endogenous p53, overexpression of mutant p53 led to an increase in HIV-1 replication. Thus, these data indicate a possible functional role for wt-p53 and mutant p53 proteins in the control of HIV-1 replication patterns and proviral latency.
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PMID:The tumor suppressor protein p53 strongly alters human immunodeficiency virus type 1 replication. 820 5


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