Abstract
[en] 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.
Original language | English |
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Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 102 |
Issue number | 29 |
DOIs | |
Publication status | Published - 2005 |
Externally published | Yes |
Keywords
- Sciences de la santé humaine => Oncologie
- Animals
- Apoptosis/drug effects
- B-Lymphocytes/metabolism
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- Gene Expression Regulation, Viral/drug effects
- Hela Cells
- Histone Deacetylases/antagonists inhibitors
- Humans
- Leukemia Virus, Bovine/metabolism
- Leukemia, Lymphoid/therapy
- Leukocytes, Mononuclear/metabolism
- Luciferases
- Lymphocyte Count
- Proviruses/metabolism
- Remission Induction
- Sheep
- Valproic Acid/pharmacology/therapeutic use