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 ability of the human immunodeficiency virus (HIV) to replicate in CD+ T lymphocytes and mononuclear phagocytes(MP) is strongly influenced by immunoregulatory cytokines. In the T cell system, interleukin-2 (IL-2) provides a mitogenic signal leading to both cell proliferation and virus replication. Among other HIV-inductive cytokines, only tumor necrosis factor-alpha or -beta (TNF-alpha/-beta) have been shown thus far to trigger virus expression both in T cells and MP. The mechanism of action of TNF involves the activation of the cellular transcription factor NF-kB which binds to specific consensus sequences present in the enhancer region of the HIV proviral LTR. In addition, several other cytokines (including colony stimulating factors, IL-1, IL-3, and IL-6) have demonstrated upregulatory effects on HIV production in MP, whereas nonimmune interferons (INF-alpha/-beta) have been shown to suppress HIV replication in T cells and MP by acting at different phases in the virus life cycle. Finally, cytokines such as TGF-beta, IFN-gamma, and IL-4 have demonstrated either upregulatory or suppressive effects on virus expression depending on the experimental conditions. This scenario indicates that HIV expression is under the control of a complex network of immunoregulatory cytokines, in addition to its own endogenous regulatory proteins, suggesting that new pharmacologic strategies may be aimed at either mimicking or interrupting cytokine-dependent virus expression. In this regard, a number of different physiologic and pharmacologic agents capable of interfering with cytokine-mediated events, including glucocorticoids, anti-oxidants, such as N-Acetyl-L-Cysteine (NAC), and retinoic acid (RA) have already been shown to profoundly affect HIV replication in vitro.
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PMID:The effect of cytokines and pharmacologic agents on chronic HIV infection. 154 Apr 7

We have previously shown that the human immunodeficiency virus type 1 (HIV-1) Tat protein can activate a synthetic promoter containing consensus-binding sites for the cellular transcription factor Sp1. In this report, we show that a GAL-Tat fusion protein targeted via GAL4 DNA-binding sites can also trans activate an HIV-1 LTR promoter independently of the trans-activation response region. To show that the trans activation of the promoter by Tat directly involves the Sp1 protein, we have targeted a GAL-Sp1 fusion protein to the long terminal repeat promoter via upstream GAL4-binding sites. In the presence of Tat and GAL-Sp1, the promoter is synergistically trans activated at the transcriptional level, indicating that Tat and Sp1 functionally interact to trans activate the HIV-1 promoter. The Sp1 synergism is relatively specific, since another chimeric transcriptional activator, GAL-VP16, does not appear to be significantly synergistic with Tat.
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PMID:Synergistic activation of the human immunodeficiency virus type 1 promoter by the viral Tat protein and cellular transcription factor Sp1. 158 36

Recent findings have indicated that megakaryocytes may be susceptible to human immunodeficiency virus (HIV) infection, suggesting a potential role for megakaryocytes as viral reservoirs in HIV-infected patients. We report that the megakaryocytic cell line Dami could be productively infected with the HTLV III-B strain of HIV-1, in 26 different experiments (results of 16 experiments are reported); productive infection lasted up to 30 weeks. Despite a lack of detectable surface expression of the CD4 molecule and very low levels of CD4 mRNA, between 40% and 60% of megakaryocytic cells produced viral proteins after contact with HIV-1. Neither cytopathogenic effects nor syncytial formation was observed. Production of high levels of functional viral particles was indicated by analysis of p24 protein levels, reverse transcriptase activity, ultrastructural studies, and the capacity of supernatants from infected Dami cells to infect the Molt-4 T-lymphocytic cell line. HIV-1 RNA and protein levels in infected Dami cells were enhanced by treatment with tumor necrosis factor-alpha (TNF-alpha), and decreased by treatment with interferon-alpha (IFN-alpha) and IFN-gamma. Transient transfection of the megakaryocytic cells with various constructs of the HIV-1 promoter (LTR) linked to the luciferase reporter gene suggested that the effect of TNF-alpha was related, as in monocytic and T-cell lines, to transactivation of the enhancer region of the HIV-1 LTR. These findings indicate that signals provided by the immune system may modulate HIV-1 expression in cells of the megakaryocytic lineage.
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PMID:Productive human immunodeficiency virus-1 infection of megakaryocytic cells is enhanced by tumor necrosis factor-alpha. 158 16

We have analyzed the transcriptional activity of the human immunodeficiency virus type I (HIV-1) LTR promoter in the fission yeast Schizosaccharomyces pombe (S.pombe). The ability of a series of 5'-deleted forms of the HIV-1 LTR promoter to direct transcription of the chloramphenicol acetyltransferase reporter gene was studied. We found that the HIV-1 promoter is functional in S.pombe and that deletion of sequences upstream of the NF-kB binding site previously identified to contain the negative regulatory element (NRE) in mammalian cells, resulted in about thirty-fold increase in transcriptional activity. Sequences in the HIV-1 promoter that bind NF-kB were found to be essential for transcriptional activation in S.pombe. In mammalian cells, transactivation of the HIV-1 LTR requires TAR sequences and the viral Tat protein. In fission yeast, Tat failed to transactivate the HIV-1 LTR, suggesting that S.pombe may lack a cellular factor(s) required for the Tat transactivation process.
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PMID:Transcriptional activity of the human immunodeficiency virus-1 LTR promoter in fission yeast Schizosaccharomyces pombe. 159 18

Levels of trans activation of the human immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR) by the virally encoded transactivator Tat show marked species-specific differences. For example, levels of transactivation observed in Chinese hamster ovary (CHO) rodent cells are 10-fold lower than those in human cells or in CHO cells that contain the human chromosome 12. Thus, the human chromosome 12 codes for a protein or proteins that are required for optimal Tat activity. Here, the function of these cellular proteins was analyzed by using a number of modified HIV-1 LTRs and Tats. Neither DNA-binding proteins that bind to the HIV-1 LTR nor proteins that interact with the activation domain of Tat could be implicated in this defect. However, since species-specific differences were no longer observed with hybrid proteins that contain the activation domain of Tat fused to heterologous RNA-binding proteins, optimal interactions between Tat and the trans-acting responsive RNA (TAR) must depend on this factor(s).
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PMID:Human chromosome 12 is required for optimal interactions between Tat and TAR of human immunodeficiency virus type 1 in rodent cells. 160 63

The handle region (residues 84-99) in ribonuclease HI (RNase HI) from Escherichia coli, which is rich in basic amino acid residues, was altered by alanine-scanning mutagenesis. Fifteen mutant proteins were purified to homogeneity and analyzed for the enzymatic activity. A mutation of either of 2 tryptophan residues at 85 or 90 resulted in a large increase in the Km value along with a large decrease in the Vmax value. These values probably resulted from conformational changes introduced by the mutations as indicated by the CD spectra of these mutant proteins. All other mutant enzymes had Vmax values similar to that of the wild-type enzyme. In contrast, replacement of any basic amino acid residue in the handle region, except for lysine 86, yielded proteins whose Km values were 3-5-fold higher than the wild-type enzyme. Such effects were shown to be cumulative, suggesting strongly that the cluster of positive charges in the handle region is important for the effective binding of the substrate. Interestingly, the region of human immunodeficiency virus reverse transcriptase with homology to E. coli RNase HI lacks the handle region which may account for the poor RNase H activity of the domain when separated from the polymerase domain.
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PMID:Importance of the positive charge cluster in Escherichia coli ribonuclease HI for the effective binding of the substrate. 164 12

Human cytomegalovirus (CMV) alters the growth and expression of human immunodeficiency virus-1 (HIV-1) in cell culture and may accelerate the course of AIDS in HIV-1 infected patients. CMV infection or the expression of the CMV immediate early genes has been shown to activate gene expression directed by the HIV-1 LTR. However, the cis-acting elements within the HIV-1 LTR that confer responsiveness to CMV have not been clearly delineated. We report on investigations in human fibroblasts designed to precisely map this signal. Our studies demonstrate that more than one nonoverlapping region of the HIV-1 promoter is capable of responding to CMV. Sequences 3' from -19(relative to the start of transcription) are dispensable for CMV responsiveness. We also show that in addition to immediate early region 2, immediate early region 1 is able to activate HIV-1 LTR-directed gene expression.
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PMID:Sequence requirements for activation of the HIV-1 LTR by human cytomegalovirus. 164 74

We have been studying the role of human cytomegalovirus (HCMV) as a potential cofactor in human immunodeficiency virus (HIV)-related disease. The clinical relevance of HCMV is highlighted by the fact that it is a principal viral pathogen in patients with AIDS and is known to infect the same cells as HIV. In this study, we focused on the molecular interactions between HIV and HCMV in human fibroblasts and in the human glioblastoma/astrocytoma-derived cell line U373 MG, cells which can be productively infected by both viruses. Because these cells are CD4-, we used HIV pseudotyped with a murine amphotropic retrovirus as described previously (D. H. Spector, E. Wade, D. A. Wright, V. Koval, C. Clark, D. Jaquish, and S. A. Spector, J. Virol. 64:2298-2308, 1990). Initial studies showed that when cells were preinfected with HIV (Ampho-1B) for 5 days and then superinfected with HCMV, HIV antigen production dropped significantly in the coinfected cells but continued to rise in cells infected with HIV (Ampho-1B) alone. HCMV production, however, was unaffected by the presence of HIV. Further analysis showed that HIV steady-state RNA levels and gag and env protein production were also inhibited in the presence of HCMV. The transcriptional inhibition of HIV was particularly surprising in view of the previous results of several other laboratories as well as our own that HCMV infection stimulates HIV long terminal repeat-chloramphenicol acetyltransferase (LTR-CAT) expression in transient expression assays. To investigate this further, we transfected the HIV LTR-CAT construct into either uninfected cells or cells which had been preinfected with HIV. The cells were infected with HCMV 24 h posttransfection and assayed for CAT gene expression at 48 h after HCMV infection. Although there was some stimulation of the LTR-CAT in cells that were dually infected by HIV and HCMV, it was 16-fold less than that in the cells infected only with HCMV. This suggests that in the presence of the HIV infection, the stimulation of the HIV LTR-CAT gene by HCMV is significantly reduced. Experiments with UV-irradiated HCMV and the HCMV DNA polymerase inhibitor ganciclovir showed that HCMV transcription is necessary for the reduction in HIV production to occur; however, replication of the HCMV genome or any events which take place after DNA replication are not necessary. These results, coupled with the observation that inhibition is usually first seen between 8 and 24 h after HCMV infection, suggest that an HCMV early protein is involved in repression of HIV.
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PMID:Human cytomegalovirus inhibits human immunodeficiency virus replication in cells productively infected by both viruses. 165 86

The nucleotide sequences of the envelope (env) coding regions of two strains of the feline immunodeficiency virus isolated in Zurich, Switzerland (FIVZ1, FIVZ2) have been analysed. In addition, the complete sequence of the FIVZ1 isolate has been determined. Comparisons have been made with the previously published sequences of three North American isolates (PPR and the Petaluma strains FIV34TF10 and FIV14). The isolate FIVZ1 was very similar to the Petaluma strains of FIV and may represent a clonal derivative acquired by 'contamination'. Overall there are between 2.6% and 15.1% amino acid changes in the env gene products of the five isolates. Of the Zurich isolates, FIVZ2 exhibited the greatest divergence to the other viruses and based on its genotype, phenotype and origins probably represents a new isolate of FIV. Possibly the viruses diverged only recently from a common ancestor. Some 31 of the 33 cysteine residues and 17 of the 21 potential N-linked glycosylation sites of the FIV34TF10 env gene product were conserved among all five isolates. The open reading frame 3 (ORF3, or D) which overlaps the env gene (but is encoded in a different frame) has an ATG codon downstream of a potential splice acceptor site in all five isolates, supporting the view that it encodes a viral gene product. In ORF3 of FIVZ1 a stop codon was located 16 amino acids upstream of the stop codon of ORF3 of the other isolates. The ORF4 (or G) of isolate FIVZ2, thought to be the second coding exon of an FIV rev-like gene, contained a nucleotide deletion in amino acid 45 of ORF4, resulting in a--1 frameshift at this position. Comparison of the LTR sequences of the five isolates identified conserved promoter/enhancer elements. A potential stem-loop structure was identified in the R region of the LTRs of all the isolates, despite the heterogeneity of nucleotide sequences in that region. Such structures (TAR) are present in analogous regions of other lentiviruses and are responsible for tat-mediated trans-activation.
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PMID:Identification of conserved and variable regions in the envelope glycoprotein sequences of two feline immunodeficiency viruses isolated in Zurich, Switzerland. 166 Feb 15

The sequence of the LTR-LTR circle junction of human immunodeficiency virus type 1 (HIV-1) was determined. The circle junction sequences were amplified by the polymerase chain reaction and cloned into M13 sequencing vectors. The circle junction contains 4 base pairs that are not present in the integrated provirus. We show that reverse transcription in HIV-1 initiates with the addition of a dC to the tRNA primer, suggesting that the tRNA used to initiate reverse transcription ends with the consensus CCA triplet. This indicates that the source of one of the four bases in the circle junction is probably the terminal A of the tRNA primer used to initiate reverse transcription. We propose that, in HIV-1, removal of the tRNA primer by RNase H cleavage shows an unusual specificity such that cleavage occurs between the terminal rA and the adjacent rC of the tRNA primer. These data also imply that the HIV-1 integration protein removes two bases from each end of the linear viral DNA during integration as has been described for other well-studied retroviruses.
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PMID:Sequence of the circle junction of human immunodeficiency virus type 1: implications for reverse transcription and integration. 169 9


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