Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors
| Autor: | Olivier Verlaeten, Amel-Baya Bouzar, Alix de Brogniez, Johan Wouters, Fabian Vandermeers, Luc Willems, Nicolas Gillet, Carole François, Eric Stern, Arnaud Florins, Didier M. Lambert, Annamaria Nigro |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Microbiology (medical)
medicine.drug_class Clone (cell biology) BLV HDAC inhibitor leukemia HTLV lcsh:Medicine Article In vivo Immunology and Allergy Medicine Molecular Biology B cell General Immunology and Microbiology Bovine leukemia virus biology business.industry Histone deacetylase inhibitor lcsh:R biology.organism_classification medicine.disease Virology Leukemia Infectious Diseases medicine.anatomical_structure Apoptosis Cancer research lipids (amino acids peptides and proteins) business Ex vivo |
| Zdroj: | Pathogens, Vol 1, Iss 2, Pp 65-82 (2012) Pathogens Pathogens; Volume 1; Issue 2; Pages: 65-82 Gillet, N, Vandermeers, F, Brogniez, A D, Florins, A, Nigro, A, François, C, Bouzar, A-B, STERN, E, Lambert, D M, Wouters, J & WILLEMS, L 2012, ' Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors ', Plos Pathogens, vol. 1, no. 2, pp. 65-82 . https://doi.org/10.3390/pathogens1020065 |
| ISSN: | 2076-0817 |
| Popis: | We previously proved that a histone deacetylase inhibitor (valproate, VPA) decreases the number of leukemic cells in bovine leukemia virus (BLV)-infected sheep. Here, we characterize the mechanisms initiated upon interruption of treatment. We observed that VPA treatment is followed by a decrease of the B cell counts and proviral loads (copies per blood volume). However, all sheep eventually relapsed after different periods of time and became refractory to further VPA treatment. Sheep remained persistently infected with BLV. B lymphocytes isolated throughout treatment and relapse were responsive to VPA-induced apoptosis in cell culture. B cell proliferation is only marginally affected by VPA ex vivo. Interestingly, in four out of five sheep, ex vivo viral expression was nearly undetectable at the time of relapse. In two sheep, a new tumoral clone arose, most likely revealing a selection process exerted by VPA in vivo. We conclude that the interruption of VPA treatment leads to the resurgence of the leukemia in BLV-infected sheep and hypothesize that resistance to further treatment might be due to the failure of viral expression induction. The development of more potent HDAC inhibitors and/or the combination with other compounds can overcome chemoresistance. These observations in the BLV model may be important for therapies against the related Human T-lymphotropic virus type 1. |
| Databáze: | OpenAIRE |
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