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 inhibitory effect of all-trans-retinoic acid (RA) on human immunodeficiency virus (HIV) replication upon infection was studied quantitatively using a novel bioassay system with a HTLV-I-carrying human T-cell line, MT-4. The results can be summarized as follows. The appearance of HIV antigen was significantly reduced when the cells were treated with more than 1 microgram/ml of the chemical after infection. When HIV specific plaque assay was performed to titrate the virus from the supernatant of culture treated with 10 micrograms/ml of RA no plaques were observed. When RA was applied directly in the plaque assay, significant decrease of the number of plaques was discerned showing 68, 66, 47 and 16, at doses of 0.1, 1, 5, and 10 micrograms/ml of RA, while 102 plaques were formed in the control dish. The appearance of cytopathic effects of MT-4 cells by HIV was more delayed in RA-treated cultures than in untreated cultures. Concomitant treatment of the cells with 5 micrograms/ml of RA and various concentrations of suramin resulted in the more effective inhibition of HIV replication than suramin alone. RA did not inhibit the reverse transcriptase activity (RT) of HIV directly. These data suggest that RA inhibits HIV replication by inducing an antiviral state in the cells.
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PMID:Effect of retinoic acid on the replication of human immunodeficiency virus in HTLV-I-positive MT-4 cells. 244 Dec 39

Human pluripotential embryonic teratocarcinoma cells differentially expressed gene activity controlled by the human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type I (HTLV-I) long terminal repeats (LTRs) when differentiation was induced by the morphogen all-trans retinoic acid. The alterations occurred after commitment and before the appearance of the multiple cell types characteristic of these pluripotential cells. After commitment, gene activity controlled by the HIV-1 LTR markedly increased, whereas that controlled by the HTLV-I LTR decreased. Steady-state mRNA levels and nuclear run-on transcription indicated that the increased HIV-1-directed activity during differentiation occurred posttranscriptionally, whereas the decreased HTLV-I activity was at the transcriptional level. Phorbol esters did not cause commitment but strongly enhanced expression by both viral LTRs at the transcriptional level. A specific inhibitor of protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, indicated that the enhanced activity involved the activation of protein kinase(s) C; altered cyclic nucleotide metabolism was apparently not involved. Differentiating cells gradually lost the ability to respond to phorbol ester stimulation. Experiments with a deletion mutant of the HIV-1 LTR suggested that this was due to imposition of negative regulation during differentiation that was not reversed by phorbol ester induction. Cycloheximide, with or without phorbol ester, slightly stimulated HIV-1-directed activity at the transcriptional level and massively increased the amounts of steady-state mRNA by posttranscriptional superinduction. It appeared, however, that new nuclear protein synthesis was required for maximal transcriptional stimulation by phorbol esters. Thus, changing cellular regulatory mechanisms influenced human retrovirus expression during human embryonic cell differentiation.
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PMID:Regulation of expression driven by human immunodeficiency virus type 1 and human T-cell leukemia virus type I long terminal repeats in pluripotential human embryonic cells. 283 1

Certain infections, like that with the human immunodeficiency virus-1, deplete vitamin A, and when vitamin A levels are low, immune dysfunctions establish susceptibility to further infection. Our research has focused on the immune dysfunctions that are a consequence of vitamin A deficiency and that predispose to further infection. We previously studied a helminth infection in mice, and showed that when vitamin A levels are low, the immune response develops a strong regulatory T cell imbalance with excessive T helper type-1 cell interferon (IFN)-gamma synthesis and insufficient T helper type-2 cell development and function. Here, we studied the T cell priming environment in vitamin A-deficient mice to learn how that priming environment might produce a regulatory T cell imbalance and consequently distort the ability of the immune system to respond to an infection. Our results show that during vitamin A deficiency, the priming environment included constitutive interleukin (IL)-12 and IFN-gamma transcripts, but it was devoid of constitutive IL-4 and IL-10 transcripts. Dietary all-trans-retinoic acid supplementation down-regulated the level of constitutive IL-12 and IFN-gamma transcripts. Furthermore, when T cells from naive vitamin A-deficient animals were stimulated through the T cell receptor, they produced excess IFN-gamma protein compared to T cells from control animals. In contrast, T cell stimulation failed to induce IL-4 or IL-10 secretion. The inducible IFN-gamma was largely from CD8+ T cells and all-trans-retinoic acid addition in vitro inhibited IFN-gamma production at the transcript level. Retinoic acid addition in vitro also decreased natural killer cell IFN-gamma synthesis at the transcript level. Taken together, the distorted constitutive and inducible cytokine gene expression patterns that occurred when vitamin A levels were low would be expected strongly to favor T helper type-1 development and limit T helper type-2 cell growth and differentiation, thereby limiting the animal's humoral immune response capability.
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PMID:Vitamin A deficiency results in a priming environment conducive for Th1 cell development. 761 95

T cells from human immunodeficiency virus (HIV)-infected individuals undergo spontaneous and activation-induced ex vivo apoptosis. Here we report that peripheral blood mononuclear cells (PBMCs) obtained from six HIV-infected individuals exhibited reduced ex vivo DNA fragmentation and cell death after ingestion of all-trans-retinoic acid (tRA). These effects were attenuated with continued daily RA administration, which correlated with a > 5-fold decrease in serum peak RA concentrations. Incubation of PBMCs from HIV+ individuals with tRA in vitro resulted in decreased DNA fragmentation in a subset of patients, especially those having < 500 CD4+ T cells per mm3. tRA also inhibited apoptosis of preactivated normal PBMCs induced to die by restimulation, which raises the possibility of a common mechanism between activation-induced apoptosis of activated normal PBMCs and apoptosis associated with HIV infection. Whether HIV-associated apoptosis of PBMCs, and its prevention by RA, has an impact on T-cell survival or the course of disease in patients infected with HIV will require further evaluation.
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PMID:Retinoic acid inhibition of ex vivo human immunodeficiency virus-associated apoptosis of peripheral blood cells. 770 73

A composite element that interacts with multiple nuclear receptors has been identified in the long terminal repeat (LTR) of the human immunodeficiency virus-1 (HIV-1). This element, designated nuclear receptor-responsive element (NRRE), spans the -356 to -320 LTR region and contains tightly clustered binding sites for the retinoid X receptor-alpha (RXR alpha) and for five nuclear receptors with unknown ligands, apolipoprotein AI regulatory protein-1 (ARP-1), v-erbA-related proteins-2 and -3 (EAR-2 and EAR-3), hepatocyte nuclear factor-4 (HNF-4), and nerve growth factor-inducible protein-B (NGFI-B). The NRRE also interacts with heterodimers formed between RXR alpha and either ARP-1, EAR-2, EAR-3, the retinoic acid receptor-alpha (RAR alpha), or the peroxisome proliferator-activated receptor (PPAR). Remarkably, nuclear receptor binding is conserved in the LTRs of recently evolved HIV-1 strains but it is absent in the oldest and most divergent viral isolates, raising the intriguing possibility that the NRRE has been evolved recently in the viral genome. Cotransfection experiments in human choriocarcinoma JEG-3 cells have shown that the HIV-1 LTR-driven transcription is activated by RXR alpha and RAR alpha in the presence of 9-cis- and all-trans-retinoic acid, by PPAR and RXR alpha in the presence of clofibric acid and 9-cis-retinoic acid, and by the "orphan" receptors HNF-4 and NGFI-B. These findings suggest that a complex network of nuclear receptor signaling pathways, that include 9-cis- and all-trans-retinoic acid, fatty acids, peroxisome proliferators, growth factors, membrane depolarization, and possibly other signals, converge onto the HIV-1 NRRE and may participate in modulation of viral gene expression.
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PMID:Convergence of multiple nuclear receptor signaling pathways onto the long terminal repeat of human immunodeficiency virus-1. 811 38

Retinoids regulate a broad range of biological processes through two subfamilies of nuclear retinoid receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Recently, we reported a novel type of retinoic acid antagonist (SR11335) and showed that this compound can inhibit retinoic acid (RA)-induced activation of a human immunodeficiency virus type 1 (HIV-1) promoter construct that contains a special RA response element (RARE). We have now further characterized the antagonism mediated by SR11335 and of newly synthesized structurally related compounds. Two compounds, SR11330 and SR11334, which are poor transactivators, also showed antagonist activities, inhibiting all-trans-RA (tRA) and 9-cis-RA. The retinoids inhibited transcriptional activation of RAR/RXR heterodimers effectively, while inhibition of RXR homodimers was less efficient. Inhibition was observed on several RAREs, including the TREpal, betaRARE, apoAI-RARE, and CRBPI-RARE. In addition, the antagonists inhibited tRA-induced differentiation of HL-60 cells. The antagonist did not interfere with DNA binding of the receptors. In limited proteolytic digestion assays, SR11335 induced resistance of the receptors to proteolysis, but the pattern of the degradation was not altered from that induced by tRA, suggesting that these antagonists induce their biological effects by competing with agonists for binding to RARs, thereby preventing the induction of conformational changes of the receptors necessary for transcriptional activation.
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PMID:A novel class of retinoid antagonists and their mechanism of action. 866 28

Infection of cells of the central nervous system by the human immunodeficiency virus type-1 (HIV-1) leads to HIV-1-associated neuropathology. Recent studies have demonstrated the importance of long terminal repeat (LTR) binding sites in determining the pathogenicity of HIV. Here we have investigated the presence and the functional role of transcription factors that have the potential to interact, directly or indirectly, with the nuclear receptor-responsive element in the LTR of HIV-1, in different human cell lines of the brain. Cotransfection experiments showed that in oligodendroglioma TC-620 cells, the retinoic acid receptor and the retinoid X receptor activate LTR-driven transcription in the absence of ligand. Addition of all-trans- or 9-cis-retinoic acid reverses this effect. In contrast, in astrocytoma, neuronal, and microglial cells, no significant effect of the retinoid acid pathway was detected. This retinoid response is mediated by distinct molecular interactions in the lymphotropic LAI and the neurotropic JR-CSF HIV-1 strains. Moreover, retinoid receptors were found to antagonize the chicken ovalbumin upstream promoter transcription factor- as well as the c-JUN-mediated LTR transactivation. Our findings demonstrate the importance of the retinoic acid signaling pathway and of cross-coupling interactions in the repression of HIV-1 LTR gene expression.
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PMID:Regulation of human immunodeficiency virus type 1 gene transcription by nuclear receptors in human brain cells. 879 69

Acute myeloid leukemia (AML) is infrequent in patients with human immunodeficiency virus (HIV) infection. Among AML, acute promyelocytic leukemia (APL) has been rarely described in such patients, with only one case being published. We report a 30 years-old intravenous drug abuser HIV-infected male with APL who attained complete clinical, morphological, and molecular remission after differentiation therapy with all-trans-retinoic acid (ATRA) followed by intensive chemotherapy. The results of treatment in this patient and in other AML published cases suggest that therapy for AML should not be modified because of HIV infection if patients have an adequate performance status.
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PMID:Acute promyelocytic leukemia in a HIV seropositive patient. 938 70

The rates of mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1), progression to AIDS following HIV-1 infection, and AIDS-associated mortality are all inversely correlated with serum vitamin A levels (R. D. Semba, W. T. Caiaffa, N. M. H. Graham, S. Cohn, and D. Vlahov, J. Infect. Dis. 171:1196-1202, 1995; R. D. Semba, N. M. H. Graham, W. T. Caiaffa, J. B. Margolik, L. Clement, and D. Vlahov, Arch. Intern. Med. 153:2149-2154, 1993; R. D. Semba, P. G. Miotti, J. D. Chiphangwi, A. J. Saah, J. K. Canner, G. A. Dallabetta, and D. R. Hoover, Lancet 343:1593-1596, 1994). Here we show that physiological concentrations of vitamin A, as retinol or as its metabolite, all-trans retinoic acid, repressed HIV-1Ba-L replication in monocyte-derived macrophages (MDMs). Repression required retinoid treatment of peripheral monocytes during their in vitro differentiation into MDMs. Retinoids had no repressive effect if they were added after virus infection. Retinol, as well as all-trans retinoic acid and 9-cis retinoic acid, also repressed HIV-1 long terminal repeat (LTR)-directed expression up to 200-fold in transfected THP-1 monocytes. Analysis of HIV-1 LTR deletion mutants demonstrated that retinoids were able to repress activation of HIV-1 expression by both NF-kappaB and Tat. A cis-acting sequence required for retinoid-mediated repression of HIV-1 transcription was localized between nucleotides -51 and +12 of the HIV-1 LTR within the core promoter. Protein-DNA cross-linking experiments identified four proteins specific to retinoid-treated cells that bound to the core promoter. We conclude that retinoids render macrophages resistant to virus replication by modulating the interaction of cellular transcription factors with the viral core promoter.
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PMID:Retinoid-induced repression of human immunodeficiency virus type 1 core promoter activity inhibits virus replication. 962 Oct 47

This study analyzes the influence of all-trans retinoid acid (tRA) on apoptosis of peripheral lymphocytes from human immunodeficiency virus (HIV)-positive patients. tRA inhibits the ex vivo apoptosis in T cells; a more potent effect was observed on activation-induced apoptosis. Phenotypic characterization of T cell subsets prevented from anti-CD3-induced apoptosis by tRA revealed a more potent effect on CD4 T cells. A central regulatory system for apoptosis is the CD95 system, and inappropriate induction of this pathway is thought to contribute to AIDS pathogenesis. In investigation of CD95-based apoptosis, tRA had no effect on activation-dependent induction of CD95 on T lymphocytes, but it inhibited the induction of CD95 ligand expression on anti-CD3-activated T cells. The previously reported in vivo effect of tRA inhibiting HIV-associated apoptosis and the present observations suggest that tRA could be considered to down-regulate apoptosis associated with AIDS pathogenesis.
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PMID:All-trans retinoic acid inhibition of anti-CD3-induced T cell apoptosis in human immunodeficiency virus infection mostly concerns CD4 T lymphocytes and is mediated via regulation of CD95 ligand expression. 978 Feb 48


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