Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo.
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.
Achachi
Amine
A
Molecular and Cellular Biology, Gembloux University Faculty of Agronomic Sciences, 5030 Gembloux, Belgium.
Florins
Arnaud
A
Gillet
Nicolas
N
Debacq
Christophe
C
Urbain
Patrice
P
Foutsop
Germain Manfouo
GM
Vandermeers
Fabian
F
Jasik
Agnieszka
A
Reichert
Michal
M
Kerkhofs
Pierre
P
Lagneaux
Laurence
L
Burny
Arsène
A
Kettmann
Richard
R
Willems
Luc
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D001909:Leukemia Virus, Bovine / Q000378:metabolism*; D007945:Leukemia, Lymphoid / Q000628:therapy*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008156:Luciferases; D018655:Lymphocyte Count; D011533:Proviruses / Q000378:metabolism*; D012074:Remission Induction; D012756:Sheep; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D008156:Luciferases