© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 5, 367-377,
March 7, 2001
© 2001 Oxford University Press
Somatic Mutation in Human T-Cell Leukemia Virus Type 1 Provirus and Flanking Cellular Sequences During Clonal Expansion In Vivo
Affiliations of authors: F. Mortreux, I. Leclercq, Unité 524 Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche sur le Cancer de Lille, and Unité d'Oncogenèse Virale, Centre Oscar Lambret, Lille, France; A.-S. Gabet, E. Wattel, Unité 524 INSERM, Institut de Recherche sur le Cancer de Lille, Unité d'Oncogenèse Virale, Centre Oscar Lambret, and Unité d'Oncogenèse Virale, UMR5537 Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard, Centre Léon Bérard, Lyon, France; A. Leroy, Unité d'Oncogenèse Virale, Centre Oscar Lambret; E. Westhof, Institut de Biologie Moleculaire et Cellulaire-CNRS, Strasbourg, France; A. Gessain (Unité d'Epidémiologie des Virus Oncogènes), S. Wain-Hobson (Unité de Retrovirologie Moléculaire), Institut Pasteur, Paris, France.
Correspondence to: Eric Wattel, M.D., Ph.D., Unité d'Oncogenèse Virale, UMR5537-CNRS-Université Claude Bernard, Centre Léon Bérard, 28, rue Laënnec 69373 Lyon cedex 08, France (e-mail: wattel{at}lyon.fnclcc.fr).
Background: Human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma, shows intrapatient genetic variability. Although HTLV-1 can replicate via the reverse transcription of virion RNA to a double-stranded DNA provirus (the conventional manner for retroviruses), its predominant mode of replication is via the clonal expansion (mitosis) of the infected cell. This expansion is achieved by the viral oncoprotein Tax, which keeps the infected CD4 T lymphocyte cycling. Because Tax also interferes with cellular DNA repair pathways, we investigated whether somatic mutations of the provirus that occur during the division of infected cells could account for HTLV-1 genetic variability. Methods: An inverse polymerase chain reaction strategy was designed to distinguish somatic mutations from reverse transcription-associated substitutions. This strategy allows the proviral sequences to be isolated together with flanking cellular sequences. Using this method, we sequenced 208 HTLV-1 provirus 3' segments, together with their integration sites, belonging to 29 distinct circulating cellular clones from infected individuals. Results: For 60% of the clones, 8%–80% of infected cells harbored a mutated HTLV-1 provirus, without evidence of reverse transcription-associated mutations. Mutations within flanking cellular sequences were also identified at a frequency of 2.8 x 10-4 substitution per base pair. Some of these clones carried multiple discrete substitutions or deletions, indicating progressive accumulation of mutations during clonal expansion. The overall frequency of somatic mutations increased with the degree of proliferation of infected T cells. Conclusions: These data indicate that, in vivo, HTLV-1 variation results mainly from postintegration events that consist of somatic mutations of the proviral sequence occurring during clonal expansion. The finding of substitutions in flanking sequences suggests that somatic mutations occurring after integration, presumably coupled with selection, help move the cellular clones toward a transformed phenotype, of which adult T-cell leukemia/lymphoma is the end point.
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