Expansion clonage et instabilité génétique des cellules infectées par des deltarétrovirus des primates

Dans cette thèse, nous avons montré que les deltarétrovirus, STLV-1 et HTLV-2b, se répliquent in vivo par l'expansion clonale de la cellule qu'ils infectent, ce qui pourrait expliquer leur grande stabilité génétique. L'expansion clonale jouant un rôle important dans la pathogenèse virale, nous avons étudié le profil réplicatif d'HTLV-1 chez les individus co-infectés par HTLV-1 et Strongyloïdes stercoralis (Ss), un parasite connu comme cofacteur de la leucémie/lymphome T (ATLL) associée à HTLV-1. Nous avons ainsi constaté l'intense prolifération d'un nombre restreint de clones infectés, indiquant que Ss agit comme cofacteur de l'ATLL en favorisant la multiplication des cellules porteuses du virus. Enfin, nous avons montré que Tax inhibe la transcription du gène hTERT qui est un élément limitant pour l'activité telomérase. L'expression de Tax pendant les phases précoces de la leucémogenèse pourrait ainsi favoriser l'apparition d'anomalies cytogénétiques durant le développement de l'ATLL.LYON1-BU.Sciences (692662101) / SudocSudocFranceF

High simian T-cell leukemia virus type 1 proviral loads combined with genetic stability as a result of cell-associated provirus replication in naturally infected, asymptomatic monkeys.

International audienceSimian T-cell leukemia virus type 1 (STLV-1) is a primate T cell leukemia virus of the group of oncogenic delta retroviruses. Sharing a high level of genetic homology with human T cell leukemia virus type 1 (HTLV-1), it is etiologically linked to the development of simian T cell malignancies that closely resemble HTLV-1 associated leukemias and lymphomas and might thus constitute an interesting model of study. The precise nature of STLV-1 replication in vivo remains unknown. The STLV-1 circulating proviral load of 14 naturally infected Celebes macaques (Macaca tonkeana) was measured by real-time quantitative PCR. The mean proportion of infected peripheral mononuclear cells was 7.9%, ranging from <0.4% to 38.9%. Values and distributions were closely reminiscent of those observed in symptomatic and asymptomatic HTLV-1 infected humans. Sequencing more than 32 kb of LTRs deriving from 2 animals with high proviral load showed an extremely low STLV-1 genetic variability (0.113%). This paradoxical combination of elevated proviral load and remarkable genetic stability was finally explained by the demonstration of a cell-associated dissemination of the virus in vivo. Inverse PCR (IPCR) amplification of STLV-1 integration sites evidenced clones of infected cells in all infected animals. The pattern of STLV-1 replication in these asymptomatic monkeys was indistinguishable from that of HTLV-1 in asymptomatic carriers or in patients with inflammatory diseases. We conclude that, as HTLV-1, STLV-1 mainly replicates by the clonal expansion of infected cells; accordingly, STLV-1 natural monkey infection constitutes an appropriate and promising model for the study of HTLV-1 associated leukemogenesis in vivo

Capitalizing knowledge on pests to supports the design of pesticide-free systems

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Combining literature review, tracking farmers' innovative practices, and design workshops to design pesticide-free management methods against Bruchus on lentil and Fababean

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Fate of premalignant clones during the asymptomatic phase preceding lymphoid malignancy.

peer reviewedAlmost all cancers are preceded by a prolonged period of clinical latency during which a combination of cellular events helps move carcinogen-exposed cells towards a malignant phenotype. Hitherto, investigating the fate of premalignant cells in vivo remained strongly hampered by the fact that these cells are usually indistinguishable from their normal counterparts. Here, for the first time, we have designed a strategy able to reconstitute the replicative history of the bona fide premalignant clone in an animal model, the sheep experimentally infected with the lymphotropic bovine leukemia virus. We have shown that premalignant clones are early and clearly distinguished from other virus-exposed cells on the basis of their degree of clonal expansion and genetic instability. Detectable as early as 0.5 month after the beginning of virus exposure, premalignant cells displayed a two-step pattern of extensive clonal expansion together with a mutation load approximately 6 times higher than that of other virus-exposed cells that remained untransformed during the life span of investigated animals. There was no fixation of somatic mutations over time, suggesting that they regularly lead to cellular death, partly contributing to maintain a normal lymphocyte count during the prolonged premalignant stage. This equilibrium was finally broken after a period of 18.5 to 60 months of clinical latency, when a dramatic decrease in the genetic instability of premalignant cells coincided with a rapid increase in lymphocyte count and lymphoma onset

Optimisation de la gestion des bruches et de la transformation des féveroles et lentilles pour de nouveaux produits agroalimentaires contenant des protéines végétales

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Skin human papillomavirus type 38 alters p53 functions by accumulation of ΔNp73

The E6 and E7 of the cutaneous human papillomavirus (HPV) type 38 immortalize primary human keratinocytes, an event normally associated with the inactivation of pathways controlled by the tumour suppressor p53. Here, we show for the first time that HPV38 alters p53 functions. Expression of HPV38 E6 and E7 in human keratinocytes or in the skin of transgenic mice induces stabilization of wild-type p53. This selectively activates the transcription of ΔNp73, an isoform of the p53-related protein p73, which in turn inhibits the capacity of p53 to induce the transcription of genes involved in growth suppression and apoptosis. ΔNp73 downregulation by an antisense oligonucleotide leads to transcriptional re-activation of p53-regulated genes and apoptosis. Our findings illustrate a novel mechanism of the alteration of p53 function that is mediated by a cutaneous HPV type and support the role of HPV38 and ΔNp73 in human carcinogenesis

HTLV-1 propels untransformed CD4(+) lymphocytes into the cell cycle while protecting CD8(+) cells from death

Human T cell leukemia virus type 1 (HTLV-1) infects both CD4(+) and CD8(+) lymphocytes, yet it induces adult T cell leukemia/lymphoma (ATLL) that is regularly of the CD4(+) phenotype. Here we show that in vivo infected CD4(+) and CD8(+) T cells displayed similar patterns of clonal expansion in carriers without malignancy. Cloned infected cells from individuals without malignancy had a dramatic increase in spontaneous proliferation, which predominated in CD8(+) lymphocytes and depended on the amount of tax mRNA. In fact, the clonal expansion of HTLV-1–positive CD8(+) and CD4(+) lymphocytes relied on 2 distinct mechanisms — infection prevented cell death in the former while recruiting the latter into the cell cycle. Cell cycling, but not apoptosis, depended on the level of viral-encoded tax expression. Infected tax-expressing CD4(+) lymphocytes accumulated cellular defects characteristic of genetic instability. Therefore, HTLV-1 infection establishes a preleukemic phenotype that is restricted to CD4(+) infected clones