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)

7,8-Disubstituted guanine ribonucleosides represent a class of B lymphocyte agonists that utilize a protein kinase C-independent signaling pathway. These compounds provide an alternate T helper signal for B cells and enhance antigen-specific humoral responses in the murine model and in an IL-2-dependent human model in vitro. They effectively restore high level immune responses in a variety of murine models of immunodeficiency both in vivo and in vitro. In this study we examined the potential of these compounds to improve antibody responses generated by cultured cells from patients with common variable immunodeficiency (CVI). The inability to mount normal humoral responses to antigen was confirmed in nine patients with diagnosed CVI (CVI: 37 +/- 16, normal 653 +/- 116 plaque-forming cells (PFC)/culture; P less than 0.001). In cultured lymphocytes from eight of the nine patients studied, a normal level or greater responses to nominal antigen could be elicited by antigen in the presence of the immunostimulatory nucleoside 7-methyl-8-oxoguanosine (7m8oGuo). The average response to antigen increased from 37 +/- 16 without nucleoside to 1733 +/- 488 PFC/culture in its presence (P less than 0.002). Restoration of specific immune responses was an antigen-dependent and nucleoside dose-dependent event. Signaling by 7m8oGuo rendered the response to antigen protein kinase C independent in cultures of cells from normal donors as well as from CVI patients. These data substantiate (i) that a non-C-kinase signaling pathway for antigen-dependent differentiation exists, (ii) that this pathway can function normally in B cells from patients with CVI when triggered appropriately, and (iii) that 7,8-disubstituted guanine ribonucleosides can convert a C-kinase-dependent signaling event to a C-kinase-independent signaling event. Substituted guanine ribonucleosides may have potential as immunotherapeutic agents for patients with CVI.
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PMID:Protein kinase C independent restoration of specific immune responsiveness in common variable immunodeficiency. 201 9

The human immunodeficiency virus binds to CD4+ T lymphocytes through the interaction of its envelope glycoprotein (gp120) with the CD4 molecule. The src-related protein tyrosine kinase p56lck is physically associated with CD4 and is co-immunoprecipitated by CD4 monoclonal antibody (mAb). Activators of protein kinase C (PKC) cause the dissociation of p56lck from CD4. Here we report that gp120 mAb immunoprecipitated the p56lck.CD4.gp120 complex after short term treatment (20 min) of human T lymphocytes with gp120. The p56lck that was associated with the CD4.gp120 complex was dissociated by activators of PKC. This effect was abolished by pretreatment of cells with PKC inhibitors. Thus the p56lck.CD4.gp120 immune complex immunoprecipitated by gp120 mAb behaves in a similar manner, with respect to PKC activation or inhibition, to the p56lck.CD4 complex immunoprecipitated by CD4 mAb. Short term treatment of cells with gp120, followed by gp120 mAb, resulted in an increase in the tyrosine kinase activity of p56lck associated with CD4. However, the amount of enzyme associated with CD4 remained unchanged. Long term treatment (20 h) of human T lymphocytes with gp120 resulted in the down-regulation of cell surface CD4 molecules. A parallel decrease in CD4-associated gp120 was also observed. In addition, gp120 caused the dissociation of p56lck and CD4. However, the dissociation of the p56lck from CD4 occurred at much faster rate than the down-regulation of surface CD4 molecules. Such mechanisms may account for the down-regulation of cell surface CD4 molecules and the depletion of functional CD4+ T lymphocytes which are characteristic of human immunodeficiency virus infections and acquired immune deficiency syndrome pathogenesis.
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PMID:Effect of human immunodeficiency virus gp120 glycoprotein on the association of the protein tyrosine kinase p56lck with CD4 in human T lymphocytes. 204 Jun 25

Antibodies that augment human immunodeficiency virus (HIV) infectivity of monocytes through Fc receptor (FcR) type III for IgG have been found in the blood of sero-positive patients and immunized chimpanzees. This study investigated the effect of acute and chronic HIV infection, as well as protein kinase C activators capable of up-regulating latent HIV, on the expression of these receptors. In addition, the frequency of this antibody-dependent enhancement (ADE) phenomenon was estimated using purified IgG from HIV-1 seropositive individuals at various clinical stages of infection. The existence of an FcR-dependent pathway for ADE of HIV-1 infection in peripheral blood monocytes and promonocytic U937 cells was confirmed in sera from a small subset of patients, and the phenomenon extended to FcR types I and II. The level of ADE activity was minimal, however, and no relationship between the presence or magnitude of the ADE phenomenon and clinical stage was uncovered. Finally, perturbations which activate a latent HIV infection were shown to concomitantly up-regulate FcR on infected and uninfected cells. This suggests a positive feedback loop linking up-regulation of latent infection, enhanced expression of low affinity HIV receptors such as FcR, and viral spread.
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PMID:Human immunodeficiency virus infection of monocytes: relationship to Fc-gamma receptors and antibody-dependent viral enhancement. 214 69

In a previous paper, we determined that treatment of lymphocytes with nonviable preparations of human immunodeficiency virus type 1 (HIV-1) results in an impairment of the phosphatidylinositol/protein kinase C pathway, most likely due to an inhibition of the cleavage of phosphatidylinositol bisphosphate into inositol trisphosphate and diacylglycerol, mediated by phospholipase C. Here we show that one consequence of these changes is a reduced phosphorylation of nuclear matrix-associated DNA topoisomerase II, resulting in an inhibition of the activity of this enzyme. Antibodies to the viral proteins suppressed the inhibitory effects caused by the HIV-1 preparation. Furthermore, the phytohemagglutinin A-caused augmentation of nuclear matrix-associated DNA polymerase alpha and beta activities was found to be abolished by coincubation with the HIV preparation or with the HIV-1 gp120. The phytohemagglutinin A-enhanced matrix association and processivity of DNA polymerase alpha was determined to be reduced if the lymphocytes were in contact with HIV-1 preparation. These results suggest that the reduced proliferative response of lymphocytes to phytohemagglutinin A in the presence of disrupted HIV-1 preparation is due to inhibition of at least two, perhaps separate, pathways, one involving protein kinase C resulting in a reduced phosphorylation of DNA topoisomerase II and the other changing the state of matrix association of DNA polymerase alpha and beta.
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PMID:Effect of nonviable preparations from human immunodeficiency virus type 1 on nuclear matrix-associated DNA polymerase alpha and DNA topoisomerase II activities. 215 2

A peptide sequence in the transmembrane protein of visna virus has been identified that bears a high degree of similarity to a sequence within the transmembrane protein gp41 of human immunodeficiency virus that we have previously shown to be immunosuppressive. Also within the Q (vif/sor) open reading frame of the visna virus genome is a sequence that is highly similar to the immunosuppressive sequence from the retroviral transmembrane protein p15E. We synthesized peptides containing these visna virus sequences and tested them for immunosuppressive activity, comparing them with their human immunodeficiency virus and leukemia retrovirus counterparts. Both the Q- and transmembrane-derived visna virus peptides inhibited lymphoproliferation stimulated by either interleukin-2 or the T-cell antigen receptor in a dose-dependent and sequence-specific manner. The two visna virus peptides also inhibited the enzymatic activity of protein kinase C, thus providing a possible molecular mechanism by which they inhibit immune function.
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PMID:Inhibition of lymphoproliferation and protein kinase C by synthetic peptides with sequence identity to the transmembrane and Q proteins of visna virus. 215 78

Infection of H9 cells with human immunodeficiency virus type 1 (HIV-1) was found to decrease the phosphorylation of DNA topoisomerase II during the initial phase of infection. Simultaneously, with a later overshoot of phosphorylation and the subsequent activation of DNA topoisomerase II, the production of HIV-1 started. Applying three new protein kinase C inhibitors from the class of O-alkylglycerophospholipids we demonstrated that inhibition of protein kinase C-mediated phosphorylation of DNA topoisomerase II resulted in an inhibition of HIV-1 production. Based on the differential effect of the two protein kinase C activators, phorbol ester and bryostatin, we conclude that phosphorylation of DNA topoisomerase II is mediated by the form alpha and gamma of protein kinase C. These data suggest that agents which inhibit these two forms of protein kinase C are also potential candidates for an anti-HIV therapy.
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PMID:Alteration of DNA topoisomerase II activity during infection of H9 cells by human immunodeficiency virus type 1 in vitro: a target for potential therapeutic agents. 217 25

We have used a specific phosphatase inhibitor, okadaic acid, to examine the role of two phosphatases, PP1 and PP2A, in the induction of NF-kappa B and the long terminal repeat of the human immunodeficiency virus type 1 (HIV-LTR). Treatment of Jurkat cells with okadaic acid induced NF-kappa B in nuclear extracts. The rate of induction by okadaic acid was delayed compared to the induction of NF-kappa B by phorbol myristate acetate (PMA). The induction of NF-kappa B by okadaic acid was enhanced by cycloheximide or phytohemagglutinin (PHA). In contrast to PMA, okadaic acid appeared to induce NF-kappa B independently of protein kinase C (PKC). That the NF-kappa B induced by okadaic acid was functional was demonstrated by the marked increase in CAT activity that occurred in Jurkat, BJA-B, and U251 cells that were transfected with HIV-LTR-CAT and treated with okadaic acid. The increase in CAT activity triggered by okadaic acid was dependent on the presence of the NF-kappa B sites in the long terminal repeat of HIV as assessed by deletion and mutation analysis. Similarly to its effect on the induction of NF-kappa B, PHA added together with okadaic acid resulted in a further increase in CAT activity. Somewhat surprisingly, the addition of PMA inhibited the increase in CAT activity in response to okadaic acid, which suggests that the activation of PKC may also induce inhibitory factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of nuclear factor-kappa B and the human immunodeficiency virus long terminal repeat by okadaic acid, a specific inhibitor of phosphatases 1 and 2A. 217 54

Human immunodeficiency virus (HIV) spends a significant part of the viral life cycle as a latent provirus integrated into the host genome. Activation of latent HIV-1 requires mitogenic stimulation of the cell, which increases basal viral transcription, and the HIV-1 tat protein. As tat itself dramatically increases HIV-1 gene expression, it too is presumably regulated in the latent state, and may also be activated by mitogenic stimulation. We show here that depletion of protein kinase C (PKC), which is essential to the stimulation of T cells by several mitogens, dramatically reduces HIV-1 transactivation without affecting synthesis of tat protein. Transactivation in PKC-depleted cells can be restored by transfection with a PKC expression vector. The requirement for PKC in trans-activation does not involve the PMA-responsive enhancer elements responsible for the effect of mitogens on basal transcription. Our results indicate that PKC regulates the process of HIV-1 transactivation, suggesting a key role for the mitogenic induction of trans-activation in the transition of HIV from latency to productive growth.
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PMID:Trans-activation of HIV-1 LTR-directed gene expression by tat requires protein kinase C. 218 21

Expression of a highly specific protein inhibitor for cyclic AMP-dependent protein kinases in interleukin-1 (IL-1)-responsive cells blocked IL-1-induced gene transcription that was driven by the kappa immunoglobulin enhancer or the human immunodeficiency virus long terminal repeat. This inhibitor did not affect protein kinase C-mediated gene transcription, suggesting that cyclic AMP-dependent protein kinases are involved in the signal transduction pathway for IL-1 in a number of responsive cell types.
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PMID:Involvement of cyclic AMP-dependent protein kinases in the signal transduction pathway for interleukin-1. 219 64

The chronically infected promonocytic clone U1 expresses low-to-undetectable constitutive levels of human immunodeficiency virus (HIV). Virus replication in these cells can be increased up to 25-fold by phorbol esters (phorbol-12-myristate-13-acetate), recombinant cytokines such as tumor necrosis factor-alpha, and cytokine-enriched mononuclear cell supernatants. We have tested specific activators of protein kinases (PK) and PK inhibitors (isoquinolinesulfonamide derivatives), as well as calcium-mobilizing agents, for their effect on constitutive and induced virus expression in U1 cells. Virus expression was measured by reverse transcriptase, Western blot, and nuclear run-on analysis. Activation of PKC by 1-oleyl,2-acetylglycerol, a synthetic analog of the natural ligand 1,2-diacylglycerol, and bryostatin 1 (a recently described specific PKC activator) resulted in a two- to eightfold increase in virus production. In contrast, activators of cyclic-nucleotide-dependent PKs were not effective in inducing virus expression. PK inhibitors were tested for their effect on HIV upregulation by cytokines and other inducing agents. The isoquinolinesulfonamide derivative H7, a potent inhibitor of PKC activation, effectively blocked (70 to 90%) HIV induction by cytokines and phorbol-12-myristate-13-acetate. The derivative HA1004, which is more selective for cyclic-nucleotide-dependent kinases, did not suppress viral induction. In addition, increases in intracellular calcium levels dramatically enhanced HIV production induced by both specific PKC activators and cytokines. These results indicate that activation of PKC is a common pathway involved in the upregulation of HIV expression in chronically infected cells stimulated by cytokines and other inducing agents.
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PMID:Direct and cytokine-mediated activation of protein kinase C induces human immunodeficiency virus expression in chronically infected promonocytic cells. 220 Aug 85


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