Tax gene expression and cell cycling but not cell death are selected during HTLV-1 infection in vivo.
BACKGROUND
Adult T cell leukemia results from the malignant transformation of a CD4+ lymphoid clone carrying an integrated HTLV-1 provirus that has undergone several oncogenic events over a 30-60 year period of persistent clonal expansion. Both CD4+ and CD8+ lymphocytes are infected in vivo; their expansion relies on CD4+ cell cycling and on the prevention of CD8+ cell death. Cloned infected CD4+ but not CD8+ T cells from patients without malignancy also add up nuclear and mitotic defects typical of genetic instability related to the expression of the virus-encoded oncogene tax. HTLV-1 expression is cancer-prone in vitro, but in vivo numerous selection forces act to maintain T cell homeostasis and are possibly involved in clonal selection.


RESULTS
Here we demonstrate that the HTLV-1 associated CD4+ preleukemic phenotype and the specific patterns of CD4+ and CD8+ clonal expansion are in vivo selected processes. By comparing the effects of recent (1 month) experimental infections performed in vitro and those observed in cloned T cells from patients infected for >6-26 years, we found that in chronically HTLV-1 infected individuals, HTLV-1 positive clones are selected for tax expression. In vivo, infected CD4+ cells are positively selected for cell cycling whereas infected CD8+ cells and uninfected CD4+ cells are negatively selected for the same processes. In contrast, the known HTLV-1-dependent prevention of CD8+ T cell death pertains to both in vivo and in vitro infected cells.


CONCLUSIONS
Therefore, virus-cell interactions alone are not sufficient to initiate early leukemogenesis in vivo.
Zane
Linda
L
CNRS UMR5239, Université de Lyon, Oncovirologie et Biothérapies, Centre Léon Bérard, 69008 Lyon, France.
Sibon
David
D
Jeannin
Lionel
L
Zandecki
Marc
M
Delfau-Larue
Marie-Hélène
MH
Gessain
Antoine
A
Gout
Olivier
O
Pinatel
Christiane
C
Lançon
Agnès
A
Mortreux
Franck
F
Wattel
Eric
E
D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000821:virology*; D016923:Cell Death; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D015870:Gene Expression; D016355:Genes, pX; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000821:virology*