title: Tax gene expression and cell cycling but not cell death are selected during HTLV-1 infection in vivo.
abstract: 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.
authors.affiliation: CNRS UMR5239, Université de Lyon, Oncovirologie et Biothérapies, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Linda
authors.initials: L
authors.lastname: Zane
authors.forename: David
authors.initials: D
authors.lastname: Sibon
authors.forename: Lionel
authors.initials: L
authors.lastname: Jeannin
authors.forename: Marc
authors.initials: M
authors.lastname: Zandecki
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Delfau-Larue
authors.forename: Antoine
authors.initials: A
authors.lastname: Gessain
authors.forename: Olivier
authors.initials: O
authors.lastname: Gout
authors.forename: Christiane
authors.initials: C
authors.lastname: Pinatel
authors.forename: Agnès
authors.initials: A
authors.lastname: Lançon
authors.forename: Franck
authors.initials: F
authors.lastname: Mortreux
authors.forename: Eric
authors.initials: E
authors.lastname: Wattel
mesh_terms: 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*