Physiology and Molecular Pathology of Endogenous and Infectious Retroviruses

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.

Publications

Endogenous retroviral envelopes / syncytin genes

Mousseau G, Préault N, Souquère S, Bireau C, Cassonet P, Bacquin A, Beck L, Pierron G, Jacob Y, Dupressoir A, and Heidmann T. The sodium dependent phosphate transporter PiT1/Slc20a1 is the receptor for the endogenous retroviral envelope syncytin-B involved in mouse placenta formation. J Virol 2024 Sep 17 e0091524  Editor's Pick
 
Aymoz-Bressot T, Canis M, Meurisse F, Wijkhuisen A, Favier B, Mousseau G, Dupressoir A, Heidmann T, Bacquin A. Cell-Int: a cell-cell interaction assay to identify native membrane protein interactions. Life Sci Alliance. 2024 Sep 5;7(11)

Bacquin A, Bireau C, Tanguy M, Romanet C, Vernochet C, Dupressoir A and Heidmann T (2017) A Cell Fusion-Based Screening Method Identifies Glycosylphosphatidylinositol-Anchored Protein Ly6e as the Receptor for Mouse Endogenous Retroviral Envelope Syncytin-A. J Virol Aug 24;91(18).PMID: 28679758

Blaise S, de Parseval N, Benit L, and Heidmann T (2003) Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proc Natl Acad Sci U S A 100, 13013-13018.

Buchrieser J, Degrelle SA, Couderc T, Nevers Q, Disson O, Manet C, Donahue DA, Porrot F, Hillion KH, Perthame E, Arroyo MV, Souquere S, Ruigrok K, Dupressoir A, Heidmann T, Montagutelli X, Fournier T, Lecuit M, Schwartz O. IFITM proteins inhibit placental syncytiotrophoblast formation and promote fetal demise. Science 2019 Jul 12; 365 (6449):176-180.

Cornelis G, Heidmann O, Bernard-Stoecklin S, Reynaud K, Veron G, Mulot B, Dupressoir A* and Heidmann T* (2012) Ancestral capture of syncytin-Car1, a fusogenic endogenous retroviral envelope gene involved in placentation and conserved in Carnivora. Proc. Natl. Acad. Sci. USA, Feb 14;109(7):E432-41 (*co- authors).

Cornelis G, Heidmann O, Degrelle SA, Vernochet C, Lavialle C, Letzelter C, Bernard-Stoecklin S, Hassanin H, Mulot B, Guillomot M, Hue I, Heidmann T* and Dupressoir A*. (2013) Captured retroviral envelope syncytin gene associated with the unique placental structure of higher ruminants. Proc. Natl. Acad. Sci. USA  (*co-authors) Feb 26;110(9):E828-37

Cornelis, G., Vernochet, C., Malicorne, S., Souquere, S., Tzika, A.C., Goodman, S.M., Catzeflis, F., Robinson, T.J., Milinkovitch, M.C., Pierron, G., Heidmann, O., Dupressoir, A., and Heidmann, T. (2014). Retroviral envelope syncytin capture in an ancestrally diverged mammalian clade for placentation in the primitive Afrotherian tenrecs. Proc. Natl. Acad. Sci. U. S. A 111, E4332-E4341.

Cornelis G, Vernochet C, Carradec Q, Souquere S, Mulot B, Catzeflis F, Nilsson M, Pierron G, Heidmann O, Zeller U, Dupressoir A, Heidmann T. (2015). Retroviral envelope gene captures and syncytin exaptation for a placental function in marsupials. Proc Natl Acad Sci U S A, 112 : E487-496.

Cornelis G, Funk M, Vernochet C, Leal F, Tarazona OA, Meurice G, Heidmann O, Dupressoir A, Miralles A, Ramirez-Pinilla MP, Heidmann T. An endogenous retroviral envelope syncytin and its cognate receptor identified in the viviparous placental Mabuya lizard. Proc Natl Acad Sci U S A. 2017, Dec 19;114(51):E10991-E11000 (F1000Prime Recommended, PNAS Commentary).

Coudert AE, Redelsperger F, Chabbi-Achengli Y, Vernochet C, Marty C, Decrouy X, Heidmann T, de Vernejoul MC, Dupressoir A.Role of the captured retroviral envelope syncytin-B gene in the fusion of osteoclast and giant cell precursors and in bone resorption, analyzed ex vivo and in vivo in syncytin-B knockout mice.  Bone Rep. 2019 Jul 10;11:100214.

Degrelle SA, Buchrieser J, Dupressoir A, Porrot F, Loeuillet L, Schwartz O, Fournier. T. IFITM1 inhibits trophoblast invasion and is induced in placentas associated with IFN-mediated pregnancy diseases, iScience. 2023 Jun 15;26(7):107147.

Dupressoir A, Marceau G, Vernochet C, Benit L, Kanellopoulos C, Sapin V, and Heidmann T (2005). Syncytin-A and syncytin-B, two fusogenic placenta-specific murine envelope genes of retroviral origin conserved in Muridae. Proc Natl Acad Sci U S A 102, 725-730.

Dupressoir A, Vernochet C, Bawa O, Harper F, Pierron G, Opolon P, and Heidmann T (2009). Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene. Proc Natl Acad Sci U S A 106, 12127-12132.

Dupressoir A, Vernochet C, Harper F, Guégan, J, Dessen, P, Pierron G, Heidmann T. (2011) A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast. Proc. Natl. Acad. Sci. USA 2011, Nov 15, 108: E1164-73.

Esnault C, Cornelis G, Heidmann O, Heidmann T. Differential evolutionary fate of an ancestral primate endogenous retrovirus envelope gene, the EnvV syncytin, captured for a function in placentation. PLoS Genet. 2013 Mar;9(3):e1003400. doi: 10.1371/journal.pgen.1003400. Epub 2013 Mar 28.

Funk M, Cornelis G, Vernochet C, Heidmann O, Dupressoir A, Conley A, Glickman S, Heidmann T. Capture of a Hyena-Specific Retroviral Envelope Gene with Placental Expression Associated in Evolution with the Unique Emergence among Carnivorans of Hemochorial Placentation in Hyaenidae. J Virol. 2019 Feb 5;93(4):e01811-18

Heidmann, O., Vernochet, C., Dupressoir, A., and Heidmann, T. (2009). Identification of an endogenous retroviral envelope gene with fusogenic activity and placenta-specific expression in the rabbit: a new "syncytin" in a third order of mammals. Retrovirology 6, 107.

Heidmann O, Béguin A, Paternina J, Berthier R, Deloger M, Bawa O, Heidmann T. HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors. Proc Natl Acad Sci U S A. 2017, Aug 8;114(32):E6642-E6651

Heidmann O, Béguin A, Paternina J, Berthier R, Deloger M, Bawa O, Heidmann T. HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors. Proc Natl Acad Sci U S A. 2017 Aug 8;114(32).

Kasperek A,, Béguin A, Bawa O, De Azevedo K, Job B, Massard C, Scoazec J-Y, Heidmann T, Heidmann O. Therapeutic potential of the human endogenous retroviral envelope protein HEMO: a pan cancer analysis. Mol Oncol. 2022 Apr;16(7):1451-1473. doi: 10.1002/1878-0261.13069. Epub 2021 Oct 11.

Lavialle, C., Cornelis, G., Dupressoir, A., Esnault, C., Heidmann, O., Vernochet, C., and Heidmann, T. (2013). Paleovirology of 'syncytins', retroviral env genes exapted for a role in placentation. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368, 20120507.

Lemaître C, Harper F, Pierron G, Heidmann T, Dewannieux M. (2014). The HERV-K human endogenous retrovirus envelope protein antagonises Tetherin antiviral activity. J Virol. 2014, 88 : 13626-37.

Lemaître C, Tsang J, Bireau C, Heidmann T, Dewannieux M. A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion. PLoS Pathog. 2017 Jun 26;13(6):e1006451.

Malicorne S, Vernochet C, Cornelis G, Mulot B, Delsuc F, Heidmann O, Heidmann T, Dupressoir A. Genome-Wide Screening of Retroviral Envelope Genes in the Nine-Banded Armadillo (Dasypus novemcinctus, Xenarthra) Reveals an Unfixed Chimeric Endogenous Betaretrovirus Using the ASCT2 Receptor. J Virol. 2016 Aug 26;90(18):8132-49.

Redelsperger F, Cornelis G, Vernochet C, Tennant BC, Catzeflis F, Mulot B, Heidmann O, Heidmann T, Dupressoir A. Capture of syncytin-Mar1, a fusogenic endogenous retroviral envelope gene involved in placentation in the Rodentia squirrel-related clade. J Virol. 2014 Jul;88(14):7915-28.

Redelsperger F, Raddi N, Bacquin A, Vernochet C, Mariot V, Gache V, Blanchard-Gutton N, Charrin S, Tiret L, Dumonceaux J, Dupressoir A, Heidmann T. (2016). Genetic evidence that captured retroviral envelope syncytins contribute to myoblast fusion and muscle sexual dimorphism in mice. PloS Genet. 12(9) : e1006289.

Tsang J, Ribet D, Heidmann T, Dewannieux M. Identification of the receptor used by the ecotropic mouse GLN endogenous retrovirus. J Virol 2019  93(5), e01125-18.

Vernochet C, Redelsperger F, Harper F, Souquere S, Catzeflis F, Pierron G, Nevo E, Heidmann T and Dupressoir A. (2014) The captured retroviral envelope Syncytin-A and Syncytin-B genes are conserved in the spalacidae together with hemotrichorial placentation. Biol Reprod. 91(6):148 (F1000Prime Recommended). Featured on the front cover.

Retrotransposons

Dewannieux M, Esnault C, and Heidmann T (2003). LINE-mediated retrotransposition of marked Alu sequences. Nat Genet 35, 41-48.

Dewannieux M, Dupressoir A, Harper F, Pierron G, and Heidmann T (2004) Identification of autonomous IAP LTR retrotransposons mobile in mammalian cells. Nat Genet 36, 534-539

Dewannieux M, Harper F, Richaud A, Letzelter C, Ribet D, Pierron G, Heidmann T. (2006) Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements. Genome Res. Dec;16(12):1548-56.

Dewannieux M, Vernochet C, Ribet D, Bartosch B, Cosset FL, Heidmann T. (2011) The mouse IAP-E endogenous retrovirus can infect cells through any of the five GPI-anchored Ephrin A proteins. PLoS Pathog. Oct;7(10):e1002309.

Esnault C, Maestre J, Heidmann T: Human LINE retrotransposons generate processed pseudogenes. Nat Genet 2000, 24:363-367.

Esnault C, Heidmann O, Delebecque F, Dewannieux M, Ribet D, Hance AJ, Heidmann T, and Schwartz, O. (2005). APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses. Nature 433, 430-433.

Ribet D, Harper F, Dupressoir A, Dewannieux M, Pierron G, Heidmann T. (2008a) An infectious progenitor for the murine IAP retrotransposon: emergence of an intracellular genetic parasite from an ancient retrovirus. Genome Res. Apr;18(4):597-609.

Ribet D, Louvet-Vallée S, Harper F, de Parseval N, Dewannieux M, Heidmann O, Pierron G, Maro B, Heidmann T. (2008c) Murine endogenous retrovirus MuERV-L is the progenitor of the "orphan" epsilon viruslike particles of the early mouse embryo. J Virol. Feb;82(3):1622-5.

Immunosuppression

Mangeney M, and Heidmann T (1998). Tumor cells expressing a retroviral envelope escape immune rejection in vivo. Proc Natl Acad Sci U S A 95, 14920-14925.

Mangeney M, Pothlichet J, Renard M, Ducos B, and Heidmann T (2005). Endogenous Retrovirus expression is required for murine melanoma tumor growth in vivo. Cancer Res 65, 2588-2591.

Pothlichet J, Heidmann T, and Mangeney M (2006a). A recombinant endogenous retrovirus amplified in a mouse neuroblastoma is involved in tumor growth in vivo. Int J Cancer 119, 815-822.

Mangeney M, Renard M, Schlecht-Louf G, Bouallaga I, Heidmann O, Letzelter C, Richaud A, Ducos B, Heidmann T. Placental syncytins: Genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20534-9.

Nzounza P, Martin G, Dereuddre-Bosquet N, Najburg V, Gosse L, Ruffié C, Combredet C, Petitdemange C, Souquère S, Schlecht-Louf G, Moog C, Pierron G, Le Grand R, Heidmann T, Tangy F.A recombinant measles virus vaccine strongly reduces SHIV viremia and virus reservoir establishment in macaques. NPJ Vaccines. 2021 Oct 22;6(1):123

Schlecht-Louf G, Renard M, Mangeney M, Letzelter C, Richaud A, Ducos B, Bouallaga I, Heidmann T. Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3782-7

Schlecht-Louf G, Mangeney M, El-Garch H, Lacombe V, Poulet H, Heidmann T. A targeted mutation within the feline leukemia virus (FeLV) envelope protein immunosuppressive domain to improve a canarypox virus-vectored FeLV vaccine. J Virol. 2014 Jan;88(2):992-1001.

Patent : Polypeptide sequence involved in the modulation of the immunosupressive effect of viral proteins. Heidmann T. & Poulet H. US CIP n°13/399 208. Publication Date June 2014.

Patent : Mutated lentiviral Env proteins and their use as drugs. International Application Number: PCT/EP2012/074835. International. Patent number: WO 2013/083799. International Publication Date 13 June 2013.

Patent : Mutated non-primate lentiviral Env proteins and their use as drugs. European Application Number: EP 13305767.9. International Publication Date: 7 June 2014.

CAR-T therapy

Marchais M, Simula L, Phayanouvong M, Mami-Chouaib F, Bismuth G, Decroocq J, Bouscary D, Dutrieux J, Mangeney M. FOXO1 Inhibition Generates Potent Nonactivated CAR T Cells against Solid Tumors. Cancer Immunol Res. 2023 Nov 1;11(11):1508-1523

Patent: “Method to generate more efficient CAR-T cells”, PCT/EP2023/073799, Mangeney M. et al

Oncolytic viruses

Patent: GB2315834.8 /  2023 06 23 / « Oncolytic viruses and their uses » / Dupressoir A. et al

Electron microscopy

Yamazaki T, Souquere S, Chujo T, Kobelke S, Chong YS, Fox AH, Bond CS, Nakagawa S, Pierron G, Hirose T. Functional Domains of NEAT1 Architectural lncRNA Induce Paraspeckle Assembly through Phase Separation. Mol Cell. 2018; 70(6):1038-1053.e7.

Yamazaki T, Yamamoto T, Yoshino H, Souquere S, Nakagawa S, Pierron G, Hirose T. Paraspeckles are constructed as block copolymer micelles. EMBO J. 2021; 40(12):e107270.

Takakuwa H, Yamazaki T, Souquere S, Adachi S, Yoshino H, Fujiwara N, Yamamoto T, Natsume T, Nakagawa S, Pierron G, Hirose T. Shell protein composition specified by the lncRNA NEAT1 domains dictates the formation of paraspeckles as distinct membraneless organelles. Nat Cell Biol. 2023; 25(11):1664-1675.

Lab members

Team leader: Anne Dupressoir

Researchers :

• Anne DUPRESSOIR, CRHC Inserm
• Odile HEIDMANN, CRCN CNRS
• Thierry HEIDMANN, DREM
• Gérard PIERRON, DREM
• Marianne MANGENEY, CRHC CNRS
• Agathe BACQUIN, Researcher
• Grégoire MARTIN, Researcher
• Guillaume MOUSSEAU, Researcher
• Baptiste ROELENS, Researcher
• Jhen TSANG, Researcher
• Maude MARCHAIS, Researcher

ITA :

• Anthony BEGUIN, AI
• Corinne LECLERCQ, TCN
• Julie HELAL,  apprentice

PhD students :

• Thibaud AYMOZ-BRESSOT
• Guillaume HOLLAENDER
• Auriane PELSMA
• Noé HERBEL
• Théo HERAYL

Interns :

• Roxane ROUZIERE, M2
• Laurene DREANO, M2
• Antoine ROBERT, M2
• Eva BOSSET, M1

Administrative manager :  Seila CHAP, AI CNRS