Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression
            <i>in vivo</i>

Achachi, Amine; Florins, Arnaud-Francois; Gillet, Nicolas; Debacq, Christophe; Urbain, Patrice; Foutsop, Germain Manfouo; Vandermeers, Fabian; Jasik, Agnieszka; Reichert, M.; Kerkhofs, Pierre; Lagneaux, Laurence; Burny, Arsène; Kettmann, Richard; Willems, Luc

doi:10.1073/pnas.0504248102

Cited by 66 publications

(85 citation statements)

References 43 publications

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“…Therefore, valproate has been selected to evaluate the effectiveness of a gene activation chemotherapy in leukemic sheep. Indeed, valproate effectively activates BLV gene expression in transient transfection experiments and in short-term cultures of primary B-lymphocytes (81). In vivo, valproate administration, in the absence of any other cytotoxic drug, is efficient for the treatment of leukemia/lymphoma in sheep, demonstrating the proof-of-concept of a therapy that targets the expression of viral and/or cellular genes.…”

Section: Modulation Of Viral Expression As Therapymentioning

confidence: 93%

Cell dynamics and immune response to BLV infection: a unifying model

Florins¹

2007

Front Biosci

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Section: Modulation Of Viral Expression As Therapymentioning

confidence: 93%

Cell dynamics and immune response to BLV infection: a unifying model

Florins¹

2007

Front Biosci

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“…Therapeutic protocols designed to affect HTLV-1-infected cell proliferation or virus replication are still ineffective. 30 A novel approach, called gene-activation therapy, has been proposed, based on preclinical trials in the bovine leukemia virus model 31 and preliminary data on HAM/TSP. 21 The principle is to activate viral gene expression by HDAC inhibitors and thereby expose virus-positive cells to the host immune response.…”

Section: Discussionmentioning

confidence: 99%

Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes

Belrose

Gross

Olindo

et al. 2011

Blood

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IntroductionHuman T-lymphotropic virus-1 (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). 1,2 Although the majority of HTLV-1-infected individuals remain asymptomatic carriers (ACs), the lifetime cumulative risk of developing ATL or HAM/ TSP is Ͻ 5%. HTLV-1-provirus integrates into the genome of infected cells, predominantly CD4 ϩ CD25 ϩ T lymphocytes, which represent the main reservoir in peripheral blood. 3 HAM/TSP, a central nervous system neuroinflammatory disease, is associated with perivascular and parenchymal infiltration of HTLV-1-infected T cells and activated cytotoxic T lymphocytes (CTLs). 4 A major determinant of HAM/TSP development is the HTLV-1-infected cell burden. The peripheral blood HTLV-1-proviral load is higher in HAM/TSP patients than AC. 5,6 Follow-up studies of HAM/TSP cohorts showed that high provirus loads were associated with rapid disease progression. [7][8][9] Those studies also demonstrated a relative stability of the HTLV-1-proviral load throughout the disease. Set-point provirus load and subsequent HAM/TSP risk are influenced by the cellular immune-response efficiency, 10 although excessive activation of HTLV-1-specific CTLs might become deleterious and contribute to central nervous system tissue damage. 4 Host-pathogen interplay is characterized by very dynamic kinetics, resulting in an equilibrium between the virus-driven clonal expansion of infected T cells 11 and tight control exerted by the immune response. 10 Tax, a transactivator protein encoded by the pX region of the HTLV-1 genome, plays a central role in disease pathogenesis. Tax activates viral transcription and also modulates many cellular signaling pathways involved in T cell activation, cycling, apoptosis or a combination. 12 Tax expression is promitotic and drives CD4 ϩ T-cell proliferation. 13 At the same time, Tax is the immunodominant target recognized by the CTL response. 14 Rapid immune elimination of Tax-expressing cells may explain the poor detection of Tax-gene products (ie, mRNA or protein) in freshly isolated peripheral blood mononuclear cells (PBMCs) from infected patients. 15-18 Short-term culture enables Tax detection and ex vivo conditions might allow Tax-expressing cells to escape immune selective pressure. 19 The current model of HTLV-1 accumulation and persistence supposes 2 steps: first, Tax expression propels CD4 ϩ T cells into cell cycling, which is well documented; and second, silencing of virus expression allows escape from immune surveillance, which remains to be elucidated. Epigenetic mechanisms might participate in silencing of HTLV-1 gene transcription. 20 Use of histone deacetylase (HDAC) inhibitors, such as valproate (2-npropylpentanoic acid, VPA), was postulated to transiently activate virus expression and thereby expose the latent virus reservoir to immune destruction. 21,22 Another avenue of research focuses on negative posttranscriptional regulators of virus expression, eg, pX-encoded Rex and p30 II...

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“…74 The effectiveness of the valproate therapy as an activator of transcription of the BLV LTR and of p24 synthesis was demonstrated in transient transfection experiments and in short-term cultures of primary B lymphocytes. 75 Indeed, treatment with valproate caused a transient increase of proviral load, a decreased in lymphocyte number, and the induction of tumor regression in leukemic sheep. 75 After valproate treatment, the authors observed a slow and continuous rate of tumor cell destruction, possibly attributed to the induction of an immune response subsequent to the proviral reactivation.…”

Section: Potential Therapeutic Treatment For Blv-infected Cowsmentioning

confidence: 99%

“…75 Indeed, treatment with valproate caused a transient increase of proviral load, a decreased in lymphocyte number, and the induction of tumor regression in leukemic sheep. 75 After valproate treatment, the authors observed a slow and continuous rate of tumor cell destruction, possibly attributed to the induction of an immune response subsequent to the proviral reactivation. In spite of these encouraging results in the leukemic sheep, the animals remained persistently infected.…”

Section: Potential Therapeutic Treatment For Blv-infected Cowsmentioning

confidence: 99%

Bovine leukemia virus: current perspectives

Juliarena¹,

Barrios²,

Lützelschwab³

et al. 2017

VAAT

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Enzootic bovine leukosis, caused by bovine leukemia virus (BLV), is the most common neoplasm of dairy cattle. Although beef and dairy cattle are susceptible to BLV infection and BLV-associated lymphosarcoma, the disease is more commonly detected in dairy herds, mostly because of the management practices in dairy farms. The pathogenicity of BLV in its natural host, the bovine, depends mainly on the resistance/susceptibility genetics of the animal. The majority of infected cattle are asymptomatic, promoting the extremely high dissemination rate of BLV in many bovine populations. The important productive losses caused by the BLV, added to the health risk of maintaining populations with a high prevalence of infection with a retrovirus, generates the need to implement control measures. Different strategies to control the virus have been attempted. The most effective approach is to identify and cull the totality of infected cattle in the herd. However, this approach is not suitable for herds with high prevalence of infection. At present, no treatment or vaccine has proven effective for the control of BLV. Thus far, the genetic selection of resistant animals emerges as a natural strategy for the containment of the BLV dissemination. In natural conditions, most of the infected, resistant cattle can control the infection, and therefore do not pass the virus to other animals, gradually decreasing the prevalence of the herd.

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Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo

Abstract: Leukemogenic viruses like human T-lymphotropic virus and bovine leukemia virus (BLV

Cited by 66 publications

References 43 publications

Cell dynamics and immune response to BLV infection: a unifying model

Cell dynamics and immune response to BLV infection: a unifying model

Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes

Bovine leukemia virus: current perspectives

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