A dose-effect relationship for deltaretrovirus-dependent leukemogenesis in sheep

doi:10.1186/1742-4690-6-30

Retrovirology

Volume 6

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Pomier C
Alcaraz MT
Debacq C
Lançon A
Kerkhofs P
Willems L
Wattel E
Mortreux F

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Pomier C
Alcaraz MT
Debacq C
Lançon A
Kerkhofs P
Willems L
Wattel E
Mortreux F
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Research

A dose-effect relationship for deltaretrovirus-dependent leukemogenesis in sheep

Carole Pomier¹ , Maria Teresa Sanchez Alcaraz² , Christophe Debacq² , Agnes Lançon¹ , Pierre Kerkhofs⁴ , Lucas Willems² , Eric Wattel¹^,3^* and Franck Mortreux¹^*

¹CNRS FRE-3011 - Université Lyon I, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon, France

²FUSAGx, Molecular and cellular biology, Gembloux, Belgium

³Hôpital Edouard Herriot, Service d'Hématologie, Pavillon E, Lyon, France

⁴Veterinary and Agrochemical Research Centre, Department of Virology, Uccle, Belgium

author email corresponding author email* Contributed equally

Retrovirology 2009, 6:30doi:10.1186/1742-4690-6-30


Published:	3 April 2009

Abstract

Background

Retrovirus-induced tumors develop in a broad range of frequencies and after extremely variable periods of time, from only a few days to several decades, depending mainly on virus type. For hitherto unexplained reasons, deltaretroviruses cause hematological malignancies only in a minority of naturally infected organisms and after a very prolonged period of clinical latency.

Results

Here we demonstrate that the development of malignancies in sheep experimentally infected with the deltaretrovirus bovine leukemia virus (BLV) depends only on the level of BLV replication. Animals were experimentally infected with leukemogenic or attenuated, but infectious, BLV molecular clones and monitored prospectively through 8 months for viral replication. As early as 2 weeks after infection and subsequently at any time during follow-up, leukemogenic viruses produced significantly higher absolute levels of reverse transcription (RT), clonal expansion of infected cells, and circulating proviruses with RT- and somatic-dependent mutations than attenuated viruses. These differences were only quantitative, and both kinds of viruses triggered parallel temporal fluctuations of host lymphoid cells, viral loads, infected cell clonality and proliferation.

Conclusion

Deltaretrovirus-associated leukemogenesis in sheep appears to be a two-hit process over time depending on the amounts of first horizontally and then vertically expanded viruses.