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Tax gene expression and cell cycling but not cell death are selected during HTLV-1 infection in vivo

Linda Zane1, David Sibon127, Lionel Jeannin1, Marc Zandecki3, Marie-Hélène Delfau-Larue4, Antoine Gessain5, Olivier Gout6, Christiane Pinatel1, Agnès Lançon1, Franck Mortreux1 and Eric Wattel12*

Author Affiliations

1 CNRS UMR5239, Université de Lyon, Oncovirologie et Biothérapies, Centre Léon Bérard, 69008 Lyon, France

2 Hôpital Edouard Herriot, Service d'Hématologie, Pavillon E, Lyon, France

3 CHU d'Angers, Laboratoire d'Hématologie, Angers, France

4 CHU Henri Mondor, Laboratoire d'Immunologie, Créteil, France

5 Institut Pasteur, Unité d'Epidémiologie et Physiopathologie desVirus Oncogènes, Institut Pasteur, Paris, France

6 Fondation Rothschild, Service de Neurologie, Paris, France

7 Current address: Hémato-oncologie, Hôpital Saint-Louis, APHP, Université Paris VII, 1 avenue Claude Vellefaux, 75010 Paris, France

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Retrovirology 2010, 7:17  doi:10.1186/1742-4690-7-17

Published: 11 March 2010

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 theexpression 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.