Physiology and Molecular Pathology of Endogenous and Infectious Retroviruses
This team belongs to the UMR 9196 : Physiology and Molecular Pathology of Endogenous and Infectious Retroviruses
The Unit's work, historically focused on retroelements and retroviruses, has made significant contributions to:
- understanding the molecular mechanisms of retrotransposition - and regulation - of the most represented elements of eukaryotic genomes (endogenous retroviruses, LINEs, SINEs...)
- the identification and characterization of human and murine endogenous retroviruses
- the identification of endogenous retrovirus envelope genes co-opted several times during evolution: the "syncytin" genes captured for a fusogenic function in placental syncytiotrophoblast formation, and the placental envelope protein HEMO, a soluble form of which is secreted into the bloodstream.
This work has also shown that retroviral envelopes are true pharmacological effectors, with immunosuppressive/oncogenic effects essential for viral penetrance and tumor development.
These latest results have led to the development of original vaccine approaches, specifically directed against identified domains of infectious retroviruses: i.e. vaccine directed against the feline retrovirus FeLV on the US market since March 2012 (collaboration with Mérial/ Boehringer) and studies conducted on the HIV retrovirus (collab with R.Legrand, CEA Fontenay-aux- Roses and F. Tangy, Institut Pasteur) with the start-up Viroxis.
In 2011, the Unit welcomed the cell electron microscopy team (now integrated as a platform within the UMS AMMICa), which is pursuing work with the UMR -on the ultrastructure of retroviral particles and placental tissues-, as well as collaborations with Research Units in Gustave Roussy, the Paris region and abroad (e.g. Japan).
Our aim is to combine high-performance basic research - at the crossroads of retrovirology, immunology, oncology, genetics and development - with a more applied therapeutic activity.
The Unit is currently developing several lines of research:
i) Fundamental and applied studies on endogenous retrovirus envelope proteins and their impact on the evolution and physiopathology of their hosts.
- Work to identify "syncytins" in as yet unexplored placental mammals and study their impact on the -varied- physiology of placentation from an evolutionary perspective.
- Identification of receptors/interactors for these proteins, responsible for the tropism of these elements and their physiological role (3 articles in prep.).
- Characterization in humans of the non-fusogenic envelope protein, HEMO: tumor expression, therapeutic and diagnostic approaches and search for a function through partner(s) (1 article in prep.)
- Studies, using syncytin knockout mice, of the involvement of these fusogenic genes in other fundamental physiological processes involving cell fusion.
ii) Research into neoantigens/targets derived from endogenous retroviruses or their receptors, which our Unit has helped to characterize, for the development of diagnostic and therapeutic approaches directed against these elements, and the development of therapeutic ligands (e.g. nanobodies, alphaReps) via high-throughput screening or AI approaches (joint work with the start-up Viroxis).
iii) Applied research into immunosuppression mediated by retrovirus-specific domains, with vaccinology studies carried out on human retroviruses HTLV and HIV (CEA Fontenay-aux-Roses and Pasteur Institute collaboration) and the development of immunosuppressive molecules (joint work with the start-up Viroxis).
We have also initiated two innovative immuno-onco-therapy programs, stemming from our earlier work:
iv) The first program consists in developing an innovative "immuno-therapy" based on the elaboration of optimized oncolytic viruses retargeted thanks to genes previously identified in the laboratory. These viruses have proved capable of specifically infecting and destroying tumor tissue in vitro (1 article in prep.). Their efficacy is being studied in vivo in pre-clinical murine models and in phase I/II trials in spontaneous canine cancers, with a view to their development in human and veterinary medicine.
v) The second program consists of using pre-clinical murine models to validate optimized CAR-T cells as close as possible to the clinic. The study of PI3K/AKT/FOXO1 signaling pathways in T lymphocytes has recently led to improvements in the anti-tumor efficacy of CAR-T cells, and to the launch of a specific R&D program for optimized CAR-T cells derived from patients with solid tumors (e.g. pancreatic tumors), in collaboration with Gustave Roussy's clinical departments.
