Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

Matteucci, Claudia; Balestrieri, Emanuela; Macchi, Beatrice; Mastino, Antonio

doi:10.1002/jmv.20201

Cited by 7 publications

(7 citation statements)

References 27 publications

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“…However, doses Ͻ6.0 M proved to be highly specific for PKC inhibition and kept the viability of PBLs and Jurkat mostly at basal levels. Furthermore, MT-2 cells were surprisingly resilient to rottlerin-induced apoptosis (Ͼ100 M), probably due to the concomitant infection with HTLV-1, which appears to suppress apoptosis as a mechanism involved in the immortalization of the infected lymphocytes (61,62). In fact, although MT-2 cells are usually destroyed by pGeneClip-iPKC-C1 and pGeneClip vectors were used as negative controls.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes

López-Huertas

Mateos

Dı́az-Gil

et al. 2011

Journal of Biological Chemistry

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The novel protein serine/threonine kinase C (PKC) isoform is selectively expressed in T lymphocytes but not B lymphocytes, erythrocytes, polymorphonuclear neutrophils, monocytes, or macrophages (1). Other PKC isotypes (␣, ␤, ␦, ⑀, , and ) are also expressed in T cells, but PKC is essential for T cell receptor/CD3-mediated activation events (2, 3). Among novel PKCs, PKC displays the highest amino acid similarity with PKC␦, not only in the catalytic or kinase core and the diacylglycerol binding regulatory domain C1 but mainly in the NH 2 -terminal V1 domain (2). However, V3 domain of PKC is unique and does not show significant similarity with any other PKC isoforms, including PKC␦. As a result, PKC provides a molecular basis for isotype selectivity and the non-redundant activity of distinct PKC isoenzymes in T cells (4).PKC kinase activity is regulated by phosphorylation of the activation-loop residue Thr 538 on the catalytic domain during T cell activation (5). Residue Thr 538 has been described as critical for PKC catalytic activity for regulating phosphorylation of the hydrophobic motif and for enabling CD3-mediated nuclear factor-B (NF-B) activation (6). PKC also shows the unique property of being translocated to the plasma membrane lipid rafts during the immunological synapse between T cells and antigen-presenting cells (7-9). Recruitment of PKC to the immunological synapse induces the activation of intracellular signaling pathways as the mitogen-activated protein kinase and the NF-B pathway (10), essential for the regulation of T cell growth-promoting genes as IL-2 (interleukin-2) (3, 11). NF-B is also critical for the replication of the human immunodeficiency virus type 1 (HIV-1) in human blood CD4 ϩ T cells (12). The main NF-B inhibitor, IB␣, binds to the NF-B nuclear localization signal to keep it inactive in the cytoplasm in the absence of activation. Upon T cell activation, IB␣ is phosphorylated by the IB kinase complex and degraded in the proteasome (13), releasing the nuclear localization signal and allowing NF-B translocation to the nucleus, where binds to cognate sequences in inducible gene promoters (14), as the HIV-1 long terminal promoter (LTR).The main target for HIV-1 infection is the CD4 ϩ T cell population, in particular memory CD4 ϩ T cells that are generated by antigen recognition (15). The viral genome can be permanently integrated in the chromosomes of these cells, producing latent reservoirs with long half-life. HIV-1-infected memory T cells remain undetectable by the immune system and the highly active antiretroviral therapy (HAART) 4 when they are in a resting state, but they are able to release new batches of virions after

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Section: Discussionmentioning

confidence: 99%

Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes

López-Huertas

Mateos

Dı́az-Gil

et al. 2011

Journal of Biological Chemistry

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“…To shed light into this subject, some of us pioneered the experimental model of HTLV-1 infection in vitro several years ago. Our model consisted of a long-term culture of PBMCs from healthy donors after exposure to irradiated HTLV-1-infected cells as viral donors [80]. We felt that such a model was the best strategy to recapitulate in vitro what occurs naturally in vivo in HTLV-1-infected patients during the long period of immortalization and transformation that could lead to ATL.…”

Section: Latency and Leukemogenesis: Role Of Tax Hbz And Apoptosismentioning

confidence: 99%

“…Indeed, the results of this study showed that the in vitro HTLV-1 infection of mononuclear cells induces a high rate of cell proliferation during the first weeks accompanied by a heightened susceptibility to RCD through apoptosis. Moreover, there is a progressive decrease in cell death rates observed during the long-term culture phase, ultimately leading to cell immortalization [80]. Additionally, in situ hybridization showed that the cells undergoing apoptosis were indeed the infected ones, with HTLV-1 proviral DNA, rather than residual uninfected cells [80].…”

Section: Latency and Leukemogenesis: Role Of Tax Hbz And Apoptosismentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 Oncogenesis between Active Expression and Latency: A Possible Source for the Development of Therapeutic Targets

Marino-Merlo,

Grelli,

Mastino

et al. 2023

IJMS

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The human T-cell leukemia virus type 1 (HTLV-1) is the only known human oncogenic retrovirus. HTLV-1 can cause a type of cancer called adult T-cell leukemia/lymphoma (ATL). The virus is transmitted through the body fluids of infected individuals, primarily breast milk, blood, and semen. At least 5–10 million people in the world are infected with HTLV-1. In addition to ATL, HTLV-1 infection can also cause HTLV-I-associated myelopathy (HAM/TSP). ATL is characterized by a low viral expression and poor prognosis. The oncogenic mechanism triggered by HTLV-1 is extremely complex and the molecular pathways are not fully understood. However, viral regulatory proteins Tax and HTLV-1 bZIP factor (HBZ) have been shown to play key roles in the transformation of HTLV-1-infected T cells. Moreover, several studies have shown that the final fate of HTLV-1-infected transformed Tcell clones is the result of a complex interplay of HTLV-1 oncogenic protein expression with cellular transcription factors that subvert the cell cycle and disrupt regulated cell death, thereby exerting their transforming effects. This review provides updated information on the mechanisms underlying the transforming action of HTLV-1 and highlights potential therapeutic targets to combat ATL.

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“…As observed in other neoplasia, the balance between pro and anti apoptotic response is subverted in ATL cells. Preclinical studies have shown that HTLV-1 infection in vitro gives rise, in a first phase, to high proliferation and a concomitant high apoptosis rate in infected cells until, in a successive phase, the selection of immortalized clones lead to outgrowth of cells preferentially exhibiting anti-apoptotic gene expression ( Matteucci et al, 2004 ). Coherently, transformed clones from ATL patients over-express in culture the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w proteins and exhibit ex vivo a 10- to 20-fold higher sensitivity to navitoclax (ABT-263), an orally bio-available mimetic of the Bcl-2 homology domain 3 small molecule, as compared to non-HTLV-1-associated leukemic cells ( Tse et al, 2008 ).…”

Section: Targeted Biological Therapy For Atlmentioning

confidence: 99%

Future Perspectives on Drug Targeting in Adult T Cell Leukemia-Lymphoma

et al. 2018

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Human T cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia/lymphoma (ATL), HTLV-1 associated myelopathy (HAM/TSP), and of a number of inflammatory diseases with an estimated 10–20 million infected individuals worldwide. Despite a number of therapeutic approaches, a cure for ATL is still in its infancy. Conventional chemotherapy has short-term efficacy, particularly in the acute subtype. Allogeneic stem cell transplantation offers long-term disease control to around one third of transplanted patients, but few can reach to transplant. This prompted, over the past recent years, the conduction of a number of clinical trials using novel treatments. Meanwhile, new data have been accumulated on biological and molecular bases of HTLV-1 transforming and infecting activity. These data offer new rational for targeted therapies of ATL. Taking into account the double-face of ATL as an hematologic malignancy as well as a viral infectious disease, this Mini-Review seeks to provide an up-to-date overview of recent efforts in the understanding of the mechanisms involved in already used therapeutic regimens showing promising results, and in selecting novel drug targets for ATL.

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Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

Cited by 7 publications

References 27 publications

Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes

Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes

Human T-Cell Leukemia Virus Type 1 Oncogenesis between Active Expression and Latency: A Possible Source for the Development of Therapeutic Targets

Future Perspectives on Drug Targeting in Adult T Cell Leukemia-Lymphoma

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