title: Cell dynamics and immune response to BLV infection: a unifying model.
abstract: Bovine Leukemia virus (BLV) is the natural etiological agent of a lymphoproliferative disease in cattle. BLV can also be transmitted experimentally to a related ruminant species, sheep, in which the pathogenesis is more acute. Although both susceptible species develop a strong anti-viral immune response, the virus persists indefinitely throughout life, apparently at a transcriptionally silent stage, at least in a proportion of infected cells. Soon after infection, these humoral and cytotoxic activities very efficiently abolish the viral replicative cycle, permitting only mitotic expansion of provirus-carrying cells. Short term cultures of these infected cells initially indicated that viral expression protects against spontaneous apoptosis, suggesting that leukemia is a process of accumulation of long-lived cells. This conclusion was recently reconsidered following in vivo dynamic studies based on perfusions of nucleoside (bromodeoxyuridine) or fluorescent protein markers (CFSE). In sheep, the turnover rate of infected cells is increased, suggesting that a permanent clearance process is exerted by the immune system. Lymphocyte trafficking from and to the secondary lymphoid organs is a key component in the maintenance of cell homeostasis. The net outcome of the immune selective pressure is that only cells in which the virus is transcriptionally silenced survive and accumulate, ultimately leading to lymphocytosis. Activation of viral and/or cellular expression in this silent reservoir with deacetylase inhibitors causes the collapse of the proviral loads. In other words, modulation of viral expression appears to be curative in lymphocytic sheep, an approach that might also be efficient in patients infected with the related Human T-lymphotropic virus type 1. In summary, a dynamic interplay between BLV and the host immune response modulates a complex equilibrium between (i) viral expression driving (or) favoring proliferation and (ii) viral silencing preventing apoptosis. As conclusion, we propose a hypothetical model unifying all these mechanisms.
authors.affiliation: Molecular and Cellular biology, FNRS-FUSAG, Gembloux, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Florins
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gillet
authors.forename: Becca
authors.initials: B
authors.lastname: Asquith
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boxus
authors.forename: Catherine
authors.initials: C
authors.lastname: Burteau
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Twizere
authors.forename: Patrice
authors.initials: P
authors.lastname: Urbain
authors.forename: Fabian
authors.initials: F
authors.lastname: Vandermeers
authors.forename: Christophe
authors.initials: C
authors.lastname: Debacq
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Sanchez-Alcaraz
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schwartz-Cornil
authors.forename: Pierre
authors.initials: P
authors.lastname: Kerkhofs
authors.forename: Genèvieve
authors.initials: G
authors.lastname: Jean
authors.forename: Andre
authors.initials: A
authors.lastname: Théwis
authors.forename: Jack
authors.initials: J
authors.lastname: Hay
authors.forename: Franck
authors.initials: F
authors.lastname: Mortreux
authors.forename: Eric
authors.initials: E
authors.lastname: Wattel
authors.forename: Michal
authors.initials: M
authors.lastname: Reichert
authors.forename: Arsène
authors.initials: A
authors.lastname: Burny
authors.forename: Richard
authors.initials: R
authors.lastname: Kettmann
authors.forename: Charles
authors.initials: C
authors.lastname: Bangham
authors.forename: Luc
authors.initials: L
authors.lastname: Willems
mesh_terms: D000818:Animals; D000917:Antibody Formation; D017209:Apoptosis; D002417:Cattle; D016583:Enzootic Bovine Leukosis / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D001909:Leukemia Virus, Bovine / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D018448:Models, Immunological; D012756:Sheep; D012757:Sheep Diseases / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014158:Transcription, Genetic; D014779:Virus Replication