Projects and grants

The team is supported by the French Foundation for Medical Research (Fondation pour la Recherche Médicale, 2018-2021).

• Characterizing the mode of action of the viral oncoprotein Tax from HTLV-1. 

This axis includes the elucidation of the 3D structure of the Tax oncoprotein (in collaboration with Dr Guillon, MMSB, Lyon), as well as the identification of molecular partners of this protein. We are particularly interested in the centrosomal partners of Tax. The centrosome is key to the maintenance of the genetic integrity of the cell, and its functions are altered upon oncogenesis. We are developing a proximity labelling proteomics strategy known as BioID. We have identified new partners of Tax and we are currently investigating their involvement in Tax-induced centrosomal dysfunctions, and more broadly in HTLV-1-induced oncogenesis. To this end, we are using high resolution imaging, combined to high-throughput approaches such as flow imaging. We also aim to confirm our observations in clinical samples, in order to better characterize the centrosomal alterations that occur in the course of ATL development. 

In collaboration with Dr Gruffat (CIRI) and Dr Tommasino (IARC, Lyon), this strategy is expanded to the oncoproteins from the human oncogenic viruses EBV and HPV (project supported by the “Ligue Régionale contre le Cancer”). We thus aim to better understand the functional alterations of the centrosome induced by oncogenic viruses.

Contacts:

Chloé Journo (team co-leader), Janelle Gauthier (PhD student), Julien Beltramini (Master 2 student), Karim Abdelmoumen (resident physician and Master 2 student) and Florence Lormières (technical staff).

Collaborations: Christophe Guillon (MMSB, Lyon), Henri Gruffat (CIRI) and Massimo Tommasino (IARC, Lyon).

• Investigating the interactions between HTLV-1 and the innate immune system. 

We hypothesize that the interaction between HTLV-1 and the innate immune system may influence the clinical evolution of the infection. In addition to T cells that are its best characterized targets, the virus also infects monocytes and dendritic cells (DCs). Several DC subsets with specific localizations are described (in the blood, in the mucosa, in the skin, etc…). It is possible to in vitro differentiate distinct subsets from primary monocytes isolated from the blood of donors. We aim at understanding the molecular bases of the susceptibility or resistance of DC subsets to HTLV-1 infection, as well as how the virus modulates immune signaling in infected DCs (NF-ĸB and IRF3 signaling pathways). We also analyze how the virus interacts with plasmacytoid DCs, a subset specialized in anti-viral and anti-tumoral immunity (in collaboration with Dr Dreux, CIRI). Lastly, we are developing a research axis aiming at precisely describing the immunophenotype of HTLV-1-infected patients.

Contacts:

Hélène Dutartre (team co-leader), Chloé Journo (team co-leader), Auriane Carcone (PhD student), Brenda Rocamonde (post-doc), Sandrine Alais (research engineer).

Collaborations: Marlène Dreux (CIRI), Olivier Hermine (Necker Hospital, Paris), Jorge Casseb (University of São Paulo, Brazil).

• Identifying new inhibitors of viral replication. 

A high proviral load is a risk factor for the development of HTLV-1-associated pathologies. Because HTLV-1 and HIV-1 belong to the same viral family (Retroviridae), we are developing a strategy aimed at repositioning HIV-1 inhibitors, i.e. identifying anti-HIV-1 molecules that would exhibit an HTLV-1-inhibiting activity (in collaboration with Dr Alvarez, AFMB, Marseille). This strategy relies on a miniaturized screen using a luciferase test performed after co-culture in 96-well plates of infected cells and reporter target cells. The mode of action of the identified candidate molecules (i.e. the viral steps inhibited by the molecules) is also investigated. These in cellulo identified molecules are then tested in a model of non-human primates naturally infected by STLV-1 (Station of Primatology, Rousset-sur-Arc).

Contacts : Hélène Dutartre (team co-leader), Maria-Joao Sousa (Master 2 ERASMUS student), Samuel Martial (Master 2 student), Sandrine Alais (IR).

Collaborations: Karine Alvarez (AFMB, Marseille), Delphine Muriaux (IRM, Montpellier) Colline Arone (co-supervised PhD student, IRIM Montpellier),  Philippe Roingeard (Université de Tours).

Main breakthroughs in the last five years (see the “Publications” section for more details)

• Role of selective autophagy receptors, and p62 in particular, on Tax-induced constitutive activation of the NF-kB pathway (Schwob, Teruel et al, Scientific Reports 2019).
• HTLV-1 induced activation of pDCs (Assil, Futsch et al, Plos Pathog 2019).
• Role of the post-translational modifications of the anti-sense protein of HTLV-2 in its targeting to PML nuclear bodies and degradation (Dubuisson et al, Oncogene 2018).
• Characterization of DC susceptibility to HTLV-1 infection (Rizkallah et al, Plos Pathog 2017).
• Analysis of the inhibitory action of anti-HIV molecules on HTLV-1 in cellulo (Pasquier et al, Frontiers Microbiol 2018).
• Analysis of viral clonality in a case of STLV-1-associated leukemia (Turpin et al, Cancer Lett 2017).