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Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo
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Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo
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Journal Article
Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo
2005
Overview
Leukemogenic viruses like human T-lymphotropic virus and bovine leukemia virus (BLV) presumably persist in the host partly by latent integration of the provirus in a fraction of infected cells, leading to accumulative increase in the outgrowth of transformed cells. Furthermore, viral infection also correlates with a blockade of the apoptotic mechanisms concomitant with an apparent latency of the host cell. Conceptually, induction of viral or cellular gene expression could thus also be used as a therapeutic strategy against retroviral-associated leukemia. Here, we provide evidence that valproate, an inhibitor of deacetylases, activates BLV gene expression in transient transfection experiments and in short-term cultures of primary B-lymphocytes. In vivo, valproate injection into newly BLV-inoculated sheep did not abrogate primary infection. However, valproate treatment, in the absence of any other cytotoxic drug, was efficient for leukemia/lymphoma therapy in the sheep model leading to decreased lymphocyte numbers (respectively from 25.6, 35.7, and 46.5 x 10(3) cells per mm3 to 1.0, 10.6, and 24.3 x 10(3) cells per mm3 in three leukemic sheep) and tumor regression (from >700 cm3 to undetectable). The concept of a therapy that targets the expression of viral and cellular genes might be a promising treatment of adult T cell leukemia or tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy, diseases for which no satisfactory treatment exists so far.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Enzyme-Linked Immunosorbent Assay
/ Gene Expression Regulation, Viral - drug effects
/ Histone Deacetylase Inhibitors
/ Histone Deacetylases/antagonists & inhibitors
/ Humans
/ Leukemia
/ Leukemia Virus, Bovine - metabolism
/ Leukemia, Lymphoid - therapy
/ Leukocytes, Mononuclear - metabolism
/ Lymphoma
/ Oncology
/ Sciences de la santé humaine
/ Sheep
/ Tumors
/ Valproic Acid - pharmacology
/ Valproic Acid - therapeutic use
/ Valproic Acid/pharmacology/therapeutic use
/ Viruses
