Cell dynamics and immune response to BLV infection: a unifying model.
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.
Florins
Arnaud
A
Molecular and Cellular biology, FNRS-FUSAG, Gembloux, Belgium.
Gillet
Nicolas
N
Asquith
Becca
B
Boxus
Mathieu
M
Burteau
Catherine
C
Twizere
Jean-Claude
JC
Urbain
Patrice
P
Vandermeers
Fabian
F
Debacq
Christophe
C
Sanchez-Alcaraz
Maria Teresa
MT
Schwartz-Cornil
Isabelle
I
Kerkhofs
Pierre
P
Jean
Genèvieve
G
Théwis
Andre
A
Hay
Jack
J
Mortreux
Franck
F
Wattel
Eric
E
Reichert
Michal
M
Burny
Arsène
A
Kettmann
Richard
R
Bangham
Charles
C
Willems
Luc
L
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