Calcium-mediated inhibition of phorbol ester and Tax trans-activation of the human T cell leukaemia virus type 1

Copeland, Karen F.T.; Haaksma, Anthonius G.M.; Goudsmit, Jaap; Heeney, Jonathan L.

doi:10.1099/0022-1317-75-7-1623

Cited by 8 publications

(4 citation statements)

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“…Another marked difference concerns the calcium-dependent pathway. In the HTLV system, the calcium ionophore ionomycin reduced viral expression (9). This is in sharp contrast with our data for the BLV system, which show that A23187 appears to be the most potent activator of viral expression.…”

Section: Discussioncontrasting

confidence: 99%

Cellular pathways involved in the ex vivo expression of bovine leukemia virus

Kerkhofs¹,

Adam²,

Droogmans³

et al. 1996

J Virol

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Bovine leukemia virus (BLV) is the etiologic agent of enzootic bovine leukosis. The virus adopts a strategy based on the lack of viral expression in vivo: only very rare BLV-infected B lymphocytes express viral information. When the cells are isolated from animals in persistent lymphocytosis and cultivated ex vivo, a tremendous increase in viral expression occurs. To gain insight into this mechanism, we employed a general approach using chemicals that interfere specifically with cellular pathways involved in signal transduction from the cell membrane to the nucleus. Our data demonstrate that BLV expression is not correlated with the activity of protein kinase A (PKA) and is even inhibited by cyclic AMP (cAMP). The cAMP/PKA pathway is thus apparently not involved in ex vivo viral expression. In contrast, PKC appears to play a key role in this process. Phorbol myristate acetate can directly activate viral expression in B cells (in the absence of T cells). Furthermore, calphostin C, a highly specific inhibitor of PKC, partly decreases ex vivo BLV expression. Our data further demonstrate that calmodulin and calcineurin, a calmodulin-dependent phosphatase, play a key role in the induction of viral expression. The involvement of this calmodulin-dependent pathway could explain the induction of expression that cannot be assigned to PKC. Furthermore, it appears that the activation of viral expression requires a calmodulin but not a PKA-dependent pathway. These data highlight major differences between transient transfection and ex vivo experiments. Finally, despite their homologies, BLV and human T-cell leukemia virus appear to use different signal transduction pathways to induce viral expression.

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Section: Discussioncontrasting

confidence: 99%

Cellular pathways involved in the ex vivo expression of bovine leukemia virus

Kerkhofs¹,

Adam²,

Droogmans³

et al. 1996

J Virol

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“…A study using CD4 + T-cell lines experimentally infected with HTLV-1 also showed that CD3 high and CD3 low T-cells had the same capacity to express the HTLV-1 core protein (Willard-Gallo et al , 2001). Moreover, despite the structural and functional homology between HTLV-1 and BLV, treatment with a calcium ionophore reduced viral expression in HTLV-1-infected T-cells (Copeland et al , 1994), whereas it was upregulated in BLV-infected B-cells (Kerkhofs et al , 1996). Previous reports and the results obtained in the present study suggest that HTLV-1-infected T-cells and BLV-infected B-cells may use different signalling pathways and strategies to express viral antigens and to expand their infection to uninfected cells.…”

Section: Discussionmentioning

confidence: 99%

Differences in cellular function and viral protein expression between IgMhigh and IgMlow B-cells in bovine leukemia virus-infected cattle

Ikebuchi

Konnai

Okagawa

et al. 2014

Journal of General Virology

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Bovine leukemia virus (BLV) induces abnormal B-cell proliferation and B-cell lymphoma in cattle, where the BLV provirus is integrated into the host genome. BLV-infected B-cells rarely express viral proteins in vivo, but short-term cultivation augments BLV expression in some, but not all, BLV-infected B-cells. This observation suggests that two subsets, i.e. BLV-silencing cells and BLV-expressing cells, are present among BLV-infected B-cells, although the mechanisms of viral expression have not been determined. In this study, we examined B-cell markers and viral antigen expression in B-cells from BLV-infected cattle to identify markers that may discriminate BLVexpressing cells from BLV-silencing cells. The proportions of IgM high B-cells were increased in blood lymphocytes from BLV-infected cattle. IgM high B-cells mainly expressed BLV antigens, whereas IgM low B-cells did not, although the provirus load was equivalent in both subsets. Several parameters were investigated in these two subsets to characterize their cellular behaviour. Realtime PCR and microarray analyses detected higher expression levels of some proto-oncogenes (e.g. Maf, Jun and Fos) in IgM low B-cells than those in IgM high B-cells. Moreover, lymphoma cells obtained from the lymph nodes of 14 BLV-infected cattle contained IgM low or IgM " B-cells but no IgM high B-cells. To our knowledge, this is the first study to demonstrate that IgM high B-cells mainly comprise BLV-expressing cells, whereas IgM low B-cells comprise a high proportion of BLVsilencing B-cells in BLV-infected cattle. Previous reports based on the detection of BLV antigens by flow cytometry and microscopy after ex vivo cultivation Supplementary methods, five figures and four tables are available with the online version of this paper.

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“…HIV-1 LTR-mediated transcription was increased by TPA, and this response was further enhanced by the calcium (Ca 2ϩ ) ionophore ionomycin. In contrast, the induction of the HTLV-1 LTR by TPA was inhibited by ionomycin (58,59,61), suggesting that the triggering of Ca 2ϩ -dependent pathways in the cell could adversely affect virus expression. Further experiments revealed that the ionomycin-mediated inhibition was not restricted to TPA-induced activation mechanisms, since basal LTR activity and Tax-mediated activation were also compromised by ionomycin.…”

Section: Effect Of T Helper Cell Activation On Retroviral Expressionmentioning

confidence: 99%

“…This condition of immune system activation is further supported by the ability of the infected Th cell to maintain the activated state for prolonged periods in an IL-2-independent manner (146,353). We have postulated that Th-cell activation down-regulates HTLV expression (59,61). Hollsberg et al (145) have reported that HTLV-1 mediates T-cell activation through a pathway which is insensitive to the immunosuppressive cytokine TGF-␤1.…”

Section: Htlv and Atlmentioning

confidence: 99%