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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monoclonal antibodies (MAb) directed against the immunoglobulin complementary determining region 3 (CDR3)-like region of the CD4 molecule inhibit human immunodeficiency virus type 1 (HIV-1) transcription. We report here data showing that the cytoplasmic tail of CD4 is required for such inhibition to be achieved. To this aim, we studied the effect of MAb 13B8-2 treatment on (i) HIV-1 production in A2.01 cells, which express different forms of the CD4 gene, (ii) Tat-induced HIV-1 promoter activation, and (iii) mitogen-activated protein kinase (MAPK) activation, which is induced in CD4-positive cells by HIV-1 cross-linking of CD4. Inhibition of HIV production by 13B8-2 MAb treatment was consistently observed in cells expressing wild-type CD4 and cells expressing a hybrid CD4-CD8 molecule (amino acids 1 to 177 of CD4 fused to the hinge, transmembrane, and cytoplasmic domains of CD8). However, no delay in HIV-1 production was observed in cells expressing a truncated CD4 which lacks the cytoplasmic domain (CD4.401). Chloramphenicol acetyltransferase assays demonstrated that Tat-dependent activation of the HIV-1 long terminal repeat promoter was inhibited by MAb 13B8-2 in A2.01/CD4 and A2.01/CD4-CD8 but not in A2.01/CD4.401 cells. Finally, we found that MAb 13B8-2 treatment inhibited the activation of MAPK induced in A2.01/CD4 and A2.01/CD4-CD8 following cross-linking of CD4 by HIV-1.
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PMID:The cytoplasmic tail of CD4 is required for inhibition of human immunodeficiency virus type 1 replication by antibodies that bind to the immunoglobulin CDR3-like region in domain 1 of CD4. 747 7

T cell surface CD4 molecules act as co-receptors that amplify the T cell receptor (TcR)/CD3-induced signal transduction by a mechanism that requires the interaction of CD4 with p56lck tyrosine kinase (Veillette et al.; Nature 1989 338:257). Here, we demonstrate that in the absence of TcR signaling, heat-inactivated HIV-1 (HIV-HI) also elicits a cascade of events generally considered to convey a positive signal, such as protein tyrosine phosphorylation, phosphatidylinositol 4-kinase and mitogen-activated protein kinase activation. These results contribute to understand better the control that HIV may exert on its own replication or on T cell apoptosis by modulating the activation status of its target cells through its interaction with T cell surface CD4 molecules.
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PMID:HIV induces activation of phosphatidylinositol 4-kinase and mitogen-activated protein kinase by interacting with T cell CD4 surface molecules. 860 43

The serine/threonine protein kinase Raf-1 is a component of a conserved intracellular signaling cascade that controls responses to various extracellular stimuli. Transcription from several promoters, including the oncogene-responsive element in the polyomavirus enhancer, the c-fos promoter, as well as other AP-1- and Ets-dependent promoters, can be induced by Raf-1 kinase. Previously, we have shown that activated Raf-1 kinase transactivates the human immunodeficiency virus type 1 (HIV-1) long terminal repeat and have identified the NF-kappaB binding motif as a Raf-1-responsive element (RafRE). We now report that Raf-1 kinase-induced transactivation from the HIV RafRE involves the purine-rich-repeat-binding protein (GABP), which is composed of two distinct subunits (alpha and beta). GABP alpha is an Ets oncogene-related DNA-binding protein, and GABP beta contains four ankyrin-like repeats that have been shown to be essential in protein-protein interactions. In electrophoretic mobility shift assays using nuclear extracts from human Jurkat T cells, a protein-DNA complex which was supershifted with antiserum against GABP alpha and GABP beta was observed. Purified recombinant GABP alpha and beta interact with the HIV RafRE as judged from DNA binding assays. Cotransfection experiments with GABP alpha and beta and Raf-1 kinase demonstrate synergistic transactivation of the HIV-1 promoter. Point mutations in the HIV RafRE abolished the Raf-1 kinase as well as GABP alpha- and beta-induced transactivation. The observed Raf-1-GABP synergism presumably involves phosphorylation of GABP subunits, as treatment of cells with Raf-1 kinase activators serum and 12-O-tetradecanoylphorbol-13-acetate increases phosphorylation of GABP in vivo. However, GABP is not a target of Raf-1 kinase; instead, it is a substrate of mitogen-activated protein kinase (MAPK/ERK), since in vitro phosphorylation of GABP alpha and beta was achieved by the reconstituted protein kinase cascade but not with purified Raf-1 or MEK. These results suggest that Raf-1 kinase- induced activation of the HIV-1 promoter is mediated by the classical cytoplasmic cascade resulting in MAPK/ERK-mediated phosphorylation of GABP alpha and beta. Because the HIV RafRE corresponds to a region within the promoter which is essential for regulation of HIV-1 expression, the data indicate that in addition to NK-kappaB, GABP transcription factors are important for induced expression of HIV.
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PMID:Raf-1 kinase targets GA-binding protein in transcriptional regulation of the human immunodeficiency virus type 1 promoter. 864 52

It is now well established that human immunodeficiency virus type I (HIV-1) Nef contributes substantially to disease pathogenesis by augmenting virus replication and markedly perturbing T-cell function. The effect of Nef on host cell activation could be explained in part by its interaction with specific cellular proteins involved in signal transduction, including at least a member of the src family kinase, Lck, and the serine/threonine kinase, mitogen-activated protein kinase (MAPK). Recombinant Nef directly interacted with purified Lck and MAPK in coprecipitation experiments and binding assays. A proline-rich repeat sequence [(Pxx)4] in Nef occurring between amino acid residues 69 to 78 is highly conserved and bears strong resemblance to a defined consensus sequence identified as an SH3 binding domain present in several proteins which can interact with the SH3 domain of various signalling and cytoskeletal proteins. Binding and coprecipitation assays with short synthetic peptides corresponding to the proline-rich repeat sequence [(Pxx)4] of Nef and the SH2, SH3, or SH2 and SH3 domains of Lck revealed that the interaction between these two proteins is at least in part mediated by the proline repeat sequence of Nef and the SH3 domain of Lck. In addition to direct binding to full-length Nef, MAPK was also shown to bind the same proline repeat motif. Nef protein significantly decreased the in vitro kinase activity of Lck and MAPK. Inhibition of key members of signalling cascades, including those emanating from the T-cell receptor, by the HIV-1 Nef protein undoubtedly alters the ability of the infected T cell to respond to antigens or cytokines, facilitating HIV-1 replication and contributing to HIV-1-induced disease pathogenesis.
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PMID:Human immunodeficiency virus type 1 Nef binds directly to Lck and mitogen-activated protein kinase, inhibiting kinase activity. 879 6

HIV-1 Rev transactivator is readily phosphorylated at separate regions by protein kinase CK2 and MAP kinase. Protein kinase CK1 cannot replace CK2 as phosphorylating agent and cdc2 only slowly phosphorylates Rev at one of the two sites affected by MAP kinase. Mutational analysis shows that Ser-8 and, to a lesser extent, Ser-5 are phosphorylated by CK2. In contrast, a mutation (R14TV-->EED) which suppresses Rev activity dramatically enhances Rev phosphorylation either in vitro by CK2 or in vivo, suggesting that phosphorylation by CK2 could play a role in Rev down-regulation.
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PMID:Phosphorylation of HIV-1 Rev protein: implication of protein kinase CK2 and pro-directed kinases. 880 71

CD4 T-lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by MHC class II bound peptides on antigen-presenting cells. The latter provide costimulatory or accessory signals through macromolecules such as B7.1 and B7.2 which interact with coreceptors on T-cells to regulate outcomes in terms of T-cell activation or specific non-responsiveness. Complementary studies at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on antigen-presenting cell and T-cell surfaces, as an essential element in specific T-cell activation. The small xenobiotic Schiff base forming molecule tucaresol, which substitutes for the physiological donor of carbonyl groups to provide a costimulatory signal to CD4 T-helper lymphocytes (Th-cells), has been developed for testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4 Th-cell and CD8 cytotoxic T-cell responses in vivo and selectively favours a Th1-type profile of cytokine production. In murine models of virus infection and syngeneic tumour growth it has substantial therapeutic activity. Schiff base formation by tucaresol on T-cell surface amines provides a costimulatory signal to the T-cell through a mechanism that activates clofilium-sensitive K+ and Na+ transport. The signalling pathway utilised by tucaresol converges with T-cell receptor signalling at the level of MAP kinase, promoting the tyrosyl phosphorylation of ERK2 by MEK (mitogen-activated protein kinase kinase). The Schiff base forming class of immunopotentiatory drug provides the first orally active, mechanism-based immunopotentiatory agents for therapeutic testing. Tucaresol is currently undergoing pilot phase I/II clinical trials as an immunopotentiator in chronic hepatitis B virus infection, HIV infection and malignant melanoma.
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PMID:Schiff base forming drugs: mechanisms of immune potentiation and therapeutic potential. 889 54

The human immunodeficiency virus, type 1 (HIV-1) promoter is known to be activated by proinflammatory cytokines and UV light. These stimuli also activate various members of the mitogen-activated protein kinase family, including JNK/SAPK and CSBP/p38. In HeLa cells containing an integrated HIV-1 long terminal repeat (LTR) -driven reporter, we now show that the specific p38 inhibitor, SB203580, inhibits activation of the HIV-1 LTR by interleukin-1, tumor necrosis factor, UV light, and osmotic stress. Inhibition was 70-90% in all but the case of tumor necrosis factor stimulation, where inhibition was 50%. Each of these stimuli activated p38, which was inhibited by SB203580 in vitro and in vivo with an IC50 (between 0.1 and 1 microM) similar to that required to inhibit transcription. In contrast, SB203580 had no effect on JNK, which was also activated by these stimuli. The NFkappaB sites in the HIV-1 LTR were required for a response to cytokines but not to UV, and SB203580 remained capable of inhibiting UV activation in the absence of the NFkappaB sites. Studies in which SB203580 was added at different times relative to UV stimulation suggested that the critical p38-mediated phosphorylation event occurred between 2 and 4 h after UV treatment. These data indicate that p38 is required for HIV-1 LTR activation but that the action of p38 is delayed, presumably due to substrate unavailability or inaccessibility.
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PMID:Activation of the HIV-1 long terminal repeat by cytokines and environmental stress requires an active CSBP/p38 MAP kinase. 894 70

Here we report the presence of a protein kinase activity associated with human immunodeficiency virus type 1 (HIV-1) particles. We observed phosphorylation of five major proteins by the endogenous protein kinase activity. Phosphoamino acid analysis revealed phosphorylated serine and threonine residues. In addition, we observed autophosphorylation of two proteins in the presence of gamma-ATP in an in-gel phosphorylation assay. These two proteins are not linked by a disulfide bond, suggesting that two different protein kinases are associated with HIV-1 virions. Our results indicate the presence of ERK2 mitogen-activated protein kinase and of a 53,000-molecular-weight protein kinase associated with virions. Moreover, the use of different HIV strains derived from T cells and promonocytic cells, as well as the use of human T-cell leukemia virus type 1 particles, demonstrates that ERK2 is strongly associated with retrovirus particles in a cell-independent manner. Exogenous substrates, such as histone proteins, and a viral substrate, such as Gag protein, are phosphorylated by virus-associated protein kinases.
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PMID:Association of ERK2 mitogen-activated protein kinase with human immunodeficiency virus particles. 915 81

We report that human immunodeficiency virus type 1 (HIV-1) has evolved a self-perpetuating mechanism to actively generate cells permissive for productive and cytopathic infection. Only activated T cells can be productively infected, which leads to their rapid depletion (2 x 10(9)/day in an infected individual). Establishment of productive HIV-1 infection therefore requires continual activations from the large pool of quiescent T cells. Tat protein, which is secreted by infected cells, activated uninfected quiescent T cells in vitro and in vivo. These Tat-activated uninfected cells became highly permissive for productive HIV-1 infection. Activation of primary T cells by Tat protein involved integrin receptors and was associated with activation of mitogen-activated protein kinases, including ERK1 and JNK kinase. Accordingly, these primary T cells progressed from G0 to the late G1 phase of the cell cycle.
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PMID:Tat protein induces self-perpetuating permissivity for productive HIV-1 infection. 922 24

We investigated the effects of early human immunodeficiency virus-1 infection (HIV-1) on CD4- and CD28-mediated co-signaling of the T cell receptor (TCR)/CD3 complex in peripheral blood lymphocytes (PBL). CD4 ligation either alone or in conjunction with TCR occupancy resulted in abrogated signaling shown by impaired co-association of the tyrosine kinase ZAP-70 with the CD3-zeta chains in virally infected PBL. In addition, down-regulation of CD4-associated TCR signaling resulted in diminished tyrosine phosphorylation of mitogen-activated protein kinase (MAPK), a serine threonine kinase which is critically involved in the regulation of transcription factors. Furthermore, these aberrant CD4-driven signals rendered HIV-1-infected PBL susceptible to activation-induced cell death. By contrast, cross-linking of the TCR/CD3 complex with the CD28 receptor improved tyrosine phosphorylation of MAPK and salvaged infected PBL from activation-induced cell death. Our data demonstrate the importance of appropriate CD3, CD4 and CD28 co-stimulatory function to prevent apoptosis. The CD4-mediated signaling defects of the TCR could contribute to the loss of immunocompetent cells during HIV-1 infection via activation-induced cell death, whereas stimulation through the CD28 pathway could reverse these detrimental effects.
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PMID:The effects of CD3, CD4 and CD28 signaling on lymphocytes during human immunodeficiency virus-1 infection. 929 33


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