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)

Human cytomegalovirus (HCMV) has been implicated as a potential cofactor in human immunodeficiency virus type 1 (HIV-1)-related disease. Previously, we reported that HCMV inhibits HIV-1 RNA and protein synthesis in cells productively infected with both viruses but, in transient assays, activates an HIV-1 long terminal repeat-chloramphenicol acetyltransferase (LTR-CAT) construct introduced into the cell by transfection (V. Koval, C. Clark, M. Vaishnav, S. A. Spector, and D. H. Spector, J. Virol. 65:6969-6978, 1991). We show here that HCMV can also activate an infectious proviral HIV-1 genome transiently transfected into a cell. To ascertain whether integration of the HIV-1 provirus plays a role in these differential effects, we generated monoclonal and polyclonal cell lines that each contain a single integrated copy of an HIV-1 LTR-CAT construct and compared the regulatory effects of HCMV and HIV-1 infection in these cells with those occurring in the same type of cell transiently transfected with the HIV-1 LTR-CAT construct. We find that HCMV activates the transfected HIV-1 promoter 230-fold but activates the integrated promoter only 2.8- to 54-fold. In contrast, HIV-1 stimulates the integrated HIV-1 promoter 2,700- to 6,000-fold but stimulates the transfected promoter only 80-fold. Thus, the relative response of the HIV-1 promoter to HCMV and HIV-1 regulatory proteins depends upon whether it is integrated. To determine if HIV-1 gene products are necessary for the HCMV-mediated repression, we constructed cell lines containing two different stably integrated HIV-1 proviruses: one is tat- and nef-minus and transcriptionally inactive, while the other is env- and nef-minus but actively expresses the other HIV-1 gene products. Upon infection with HCMV, HIV-1 antigen production was stimulated from the inactive HIV-1 genome but inhibited from the active genome. We propose that HCMV has two separate effects on HIV-1 replication during a coinfection. One is a slight stimulatory effect which would be undetectable during an active HIV-1 infection, while the other is a net inhibitory effect that is mediated by an interaction between HCMV and HIV-1 gene products.
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PMID:Differential effects of human cytomegalovirus on integrated and unintegrated human immunodeficiency virus sequences. 785

T22 ([Tyr5,12,Lys7]-polyphemusin II) was previously synthesized by a solid-phase method and was found to have a strong anti-human immunodeficiency virus (HIV) activity, comparable to that of 3'-azido-2',3'-dideoxy-thymidine (AZT). In the present study, the solution-phase synthesis of T22 was attempted in order to produce this peptide on a large scale. An 18-residue peptide amide corresponding to the entire amino acid sequence of T22 was synthesized by assembling four peptide fragments and two amino acid derivatives, followed by thioanisole-mediated deprotection with 1 M trimethylsilyl trifluoromethanesulfonate (TMSOTf) in trifluoroacetic acid followed by air-oxidation. During this deprotection, a significant by-product derived from the transfer of the p-methoxybenzyl (MBzI) group from the sulfhydryl group of the cysteine residue to the side chain of the tryptophan residue was formed. This side reaction was found to be efficiently suppressed by adopting a two-step deprotection procedure using silver trifluoromethanesulfonate (AgOTf)-TMSOTf or trimethylsilyl bromide (TMSBr)-TMSOTf.
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PMID:Solution-phase synthesis of an anti-human immunodeficiency virus peptide, T22 ([Tyr5,12,Lys7]-polyphemusin II), and the modification of Trp by the p-methoxybenzyl group of Cys during trimethylsilyl trifluoromethanesulfonate deprotection. 789 3

Plasma concentrations of 21 amino acids were determined for 20 control subjects and 20 subjects infected with human immunodeficiency virus type 1 (HIV). Compared with the control subjects, the HIV-infected group had lower cystine, tryptophan, and methionine (decreased 67%, 52%, and 32%, respectively, P < 0.001 for each) and increased taurine (230%, P < 0.001) and lysine concentrations (30%, P < 0.001). Other amino acid concentrations changed modestly. Amounts of cystine, tryptophan, methionine, taurine, and lysine did not differ significantly between subgroups of HIV-infected subjects with > 200 (n = 6) or < 200 (n = 14) CD4+ lymphocytes per microliter, suggesting that the concentrations decrease soon after infection and change little thereafter. Activation of metabolism of cystine to taurine may explain reciprocal changes in these amino acids and known depletion of cystine and glutathione. The selective changes in amino acid profiles observed during HIV infection differ from those recognized for malnutrition or other pathological processes.
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PMID:Changes in plasma amino acid concentrations in response to HIV-1 infection. 790 26

The role of the human immunodeficiency virus (HIV-1) Nef protein in T cell activation pathways was investigated using a Jurkat CD4+ cell line stably transfected with a Nef expression vector. Secretion of IL-2 and TNF-alpha, surface expression of IL-2R, and DNA-binding activity of NF-kappa B and AP-1 (Fos/Jun) complex in response to phorbol myristate acetate, TNF-alpha, or immobilized antibodies to CD3 were monitored. These parameters were not modified by Nef expression in Jurkat cells, whereas stimulation with the same stimuli resulted in partial inhibition of LTR activation in Nef+ Jurkat cells. This inhibition was not mediated through Nef phosphorylation on Thr-15 or GTP-binding activity because mutations in critical sites did not alter this inhibition. Analysis of truncated LTRs confirmed that inhibition of LTR activation was not mediated through NF-kappa B-binding activity but through the region containing the negative responding elements (NREs). These results suggest that Nef downmodulates LTR activation without significantly inhibiting the capacity of T cells to respond to immunological activations.
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PMID:Role of HIV-1 Nef expression in activation pathways in CD4+ T cells. 791 14

Self-inactivating (SIN) retroviral vectors contain a deletion spanning most of the right long terminal repeat's (LTR's) U3 region. Reverse transcription copies this deletion to both LTRs. As a result, there is no transcription from the 5' LTR, preventing further replication. Many previously developed SIN vectors, however, had reduced titers or were genetically unstable. Earlier, we reported that certain SIN vectors derived from spleen necrosis virus (SNV) experienced reconstitution of the U3-deleted LTR at high frequencies. This reconstitution occurred on the DNA level and appeared to be dependent on defined vector sequences. To study this phenomenon in more detail, we developed an almost completely U3-free retroviral vector. The promoter and enhancer of the left LTR were replaced with those of the cytomegalovirus immediate-early genes. This promoter swap did not impair the level of transcription or alter its start site. Our data indicate that SNV contains a strong initiator which resembles that of human immunodeficiency virus. We show that the vectors replicate with efficiencies similar to those of vectors possessing two wild-type LTRs. U3-deleted vectors carrying the hygromycin B phosphotransferase gene did not observably undergo LTR reconstitution, even when replicated in helper cells containing SNV-LTR sequences. However, vectors carrying the neomycin resistance gene did undergo LTR reconstitution with the use of homologous helper cell LTR sequences as template. This supports our earlier finding that sequences within the neomycin resistance gene can trigger recombination.
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PMID:Improved self-inactivating retroviral vectors derived from spleen necrosis virus. 793 88

We have previously isolated a HeLa cell cDNA encoding a 21-kDa polypeptide that is 48% similar to transcription factor IIS. To explore the possibility that p21 plays a role in transcriptional regulation in vivo, we tested the effect of p21 expression on the synthesis of reporter chloramphenicol acetyltransferase (CAT) in transfected COS-1 cells. CAT formation under control of the Rous sarcoma virus long terminal repeat (RSV LTR) promoter was decreased nearly 20-fold in cells coexpressing p21. In contrast, CAT production under control of other sequence elements was only slightly reduced (human immunodeficiency virus type 1 LTR, simian virus 40 early promoter), unaffected (human heat shock protein of 70-kDa promoter, adenovirus major late promoter TATA box), or increased (terminal deoxynucleotidyltransferase initiator element, c-fos promoter) by p21 coexpression as compared to cells cotransfected with the parental vector. The abundance of steady-state CAT transcripts from RSV LTR was also decreased by p21 expression in a dose-dependent manner, suggesting that transcription of RSV LTR/CAT is under negative control by p21. Consistent with an effect on transcription, p21 was localized in nuclei of transfected cells. Deletion analysis of p21 indicated that the sequences essential for inhibition of RSV LTR function include the previously identified ARg/Ser-rich region and zinc finger-like motif. Proliferation of chicken embryo fibroblasts transfected with an infectious molecular clone of RSV was diminished by p21 expression, which also resulted in fewer transformed foci.
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PMID:Down-regulation of Rous sarcoma virus long terminal repeat promoter activity by a HeLa cell basic protein. 797 97

The unintegrated viral DNA found in human immunodeficiency virus type 1 infection includes linear and circular forms. We targeted the circular form containing two copies of the viral long terminal repeat (2-LTR circle) and developed specific assays to detect this molecule in peripheral blood mononuclear cells from HIV-infected patients. In vitro HIV-1 infection of peripheral blood mononuclear cells showed rapid accumulation and rapid decay of 2-LTR circular viral DNA. Examination of 2-LTR circular viral DNA levels provides a view of spreading infection based on a viral DNA form that is structurally distinct and has a known, short half-life in infected cells. In patients not receiving antiviral therapy, the levels of 2-LTR circular viral DNA and total viral DNA were significantly correlated to CD4 cell counts. Similar correlations were not observed in patients receiving zidovudine (AZT), didanosine (ddA), or zalcitabine (ddC).
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PMID:2-LTR circular viral DNA as a marker for human immunodeficiency virus type 1 infection in vivo. 797 48

One segment of the negative regulatory region of the human immunodeficiency virus long terminal repeat (HIV-LTR), nucleotides -273 to -255, is homologous to positive response elements for interleukin-2 and glucocorticoids. We demonstrate that this sequence, referred to as purine-rich response element (PRRE), acts as a classic enhancer in the context of a heterologous promoter, but serves as a functional repressor in the intact provirus, binding (a) cellular factor(s). These data suggest that certain DNA response elements in the HIV LTR serve as negative regulators only in the context of the intact LTR, presumably through interactions with other transcriptional factors, a phenomenon that might be exploited to interfere with viral gene transcription.
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PMID:Identification of a novel cell-type and context specific enhancer within the negative regulatory element of the human immunodeficiency virus type 1 long terminal repeat. 797 87

Interference with T cell activation signals by Human immunodeficiency virus (HIV) gene products is suggested to contribute to the impairment of immune functions observed in AIDS. Interleukin-2 (IL-2) and HIV share common stimulatory signals triggered during T cell activation. The role of HIV tat, which is the main enhancing factor for viral LTR, in the regulation of IL-2 gene transcription has been studied following transient expression of the tat gene in phorbol ester and calcium ionophore-activated Jurkat cells transfected with IL-2 promoter-chloramphenicol acetyltransferase reporter constructs. We observed that tat increased the IL-2 promoter transcriptional activity in response to phorbol ester and ionomycin. This tat-dependent synergism mapped to the (-279 to -263 bp) NFAT motif of the IL-2 enhancer, which was sufficient to be transactivated by tat. Our data suggest that tat links T cell activating signals to the shared IL-2 and HIV regulation. This may play a role in the early phase of HIV infection.
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PMID:Human immunodeficiency virus type-1 tat enhances interleukin-2 promoter activity through synergism with phorbol ester and calcium-mediated activation of the NF-AT cis-regulatory motif. 799 66

Human herpesvirus 6 variant A (HHV-6A) and human herpesvirus 6 variant B (HHV-6B) are closely related herpesviruses. No disease has been specifically associated with HHV-6A, whereas HHV-6B is the major etiologic agent of exanthem subitum. Both viruses may be opportunistic pathogens in the immunocompromised patient. HHV-6 genomes have low G+C contents for herpesviruses (43%); they consist of a 141-kb unique segment that is flanked by single copies of a directly repeated sequence that can vary from 10 to 13 kb. HHV-6A and HHV-6B encode homologs of many conserved herpesvirus proteins and are classified as beta-herpesviruses based on their close genetic relationship with human cytomegalovirus. HHV-6A and HHV-6B are even more closely related to the recently discovered human herpesvirus 7. HHV-6 encodes homologs of the seven genes that are essential for origin-dependent herpes simplex virus type 1 DNA replication, including the origin-binding protein, which has no clear homolog in human cytomegalovirus. The HHV-6B origin-binding protein binds to sequences with similarities to alpha-herpesvirus replication origins that lie within a genomic segment that can serve as a replication origin in transient replication assays. Both HHV-6 variants encode homologs of the adeno-associated virus type 2 Rep protein; the role of this protein during infection is unknown. HHV-6 induces synthesis of a broad range of host cell proteins, including interferon alpha, CD4, interleukin-1 beta, and tumor necrosis factor alpha, and also induces expression of the human immunodeficiency virus type 1 LTR promoter. Little is known about the process by which HHV-6 regulates gene expression.
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PMID:Molecular biology of human herpesviruses 6A and 6B. 801 36


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