Article (Scientific journals)
Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors
Gillet, Nicolas; Vandermeers, Fabian; De Brogniez, Alix et al.
2012In Pathogens, (2012-1), p. 65-82
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Keywords :
BLV; HDAC inhibitor; leukemia; HTLV
Abstract :
[en] 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.
Disciplines :
Veterinary medicine & animal health
Author, co-author :
Gillet, Nicolas ;  Université de Liège - ULiège > Chimie et bio-industries > Biologie cell. et moléc.
Vandermeers, Fabian ;  Université de Liège - ULiège > Chimie et bio-industries > Biologie cell. et moléc.
De Brogniez, Alix ;  Université de Liège - ULiège > Chimie et bio-industries > Biologie cell. et moléc.
Florins, Arnaud
Nigro, Annamaria
François, Carole
Bouzar, Amel-Baya
Verlaeten, Olivier
Stern, Eric
Lambert, Didier
Wouters, Johan
Willems, Luc  ;  Université de Liège - ULiège > Chimie et bio-industries > Biologie cell. et moléc.
Language :
English
Title :
Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors
Publication date :
08 October 2012
Journal title :
Pathogens
eISSN :
2076-0817
Publisher :
MDPI, Basel, Switzerland
Issue :
2012-1
Pages :
65-82
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 20 January 2013

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