title: A dose-effect relationship for deltaretrovirus-dependent leukemogenesis in sheep.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: CNRS FRE-3011-Université Lyon I, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon, France. ptepoms@yahoo.fr
authors.forename: Carole
authors.initials: C
authors.lastname: Pomier
authors.forename: Maria Teresa Sanchez
authors.initials: MT
authors.lastname: Alcaraz
authors.forename: Christophe
authors.initials: C
authors.lastname: Debacq
authors.forename: Agnes
authors.initials: A
authors.lastname: Lançon
authors.forename: Pierre
authors.initials: P
authors.lastname: Kerkhofs
authors.forename: Lucas
authors.initials: L
authors.lastname: Willems
authors.forename: Eric
authors.initials: E
authors.lastname: Wattel
authors.forename: Franck
authors.initials: F
authors.lastname: Mortreux