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Pathogens 2012, 1(2), 65-82; doi:10.3390/pathogens1020065
Article

Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors

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Received: 5 September 2012; in revised form: 24 September 2012 / Accepted: 2 October 2012 / Published: 8 October 2012
(This article belongs to the Special Issue Infection and Cancer)
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Abstract: 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.
Keywords: BLV; HDAC inhibitor; leukemia; HTLV BLV; HDAC inhibitor; leukemia; HTLV
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Gillet, N.; Vandermeers, F.; de Brogniez, A.; Florins, A.; Nigro, A.; François, C.; Bouzar, A.-B.; Verlaeten, O.; Stern, E.; Lambert, D.M.; Wouters, J.; Willems, L. Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors. Pathogens 2012, 1, 65-82.

AMA Style

Gillet N, Vandermeers F, de Brogniez A, Florins A, Nigro A, François C, Bouzar A-B, Verlaeten O, Stern E, Lambert DM, Wouters J, Willems L. Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors. Pathogens. 2012; 1(2):65-82.

Chicago/Turabian Style

Gillet, Nicolas; Vandermeers, Fabian; de Brogniez, Alix; Florins, Arnaud; Nigro, Annamaria; François, Carole; Bouzar, Amel-Baya; Verlaeten, Olivier; Stern, Eric; Lambert, Didier M.; Wouters, Johan; Willems, Luc. 2012. "Chemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors." Pathogens 1, no. 2: 65-82.


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