Cell-to-cell transmission of HIV-1 for dissemination in myeloid target cells

Principal investigator

Serge  Benichou

serge.benichou@inserm.fr 
Tel. +33 (0)1 40 51 65 78

Objective

Dendritic cells (DCs), macrophages as well as osteoclasts (OCs) are emerging as target cells of HIV-1 involved in virus transmission, dissemination, and establishment of persistent tissue virus reservoirs. While these myeloid cells are poorly infected by cell-free viruses because of the high expression of antiviral host cell restriction factors, cell-to-cell transfer of HIV-1 likely represents the dominant mode of virus dissemination in vivo and may allow for productive infection of these cell types (Bracq, 2018). We have demonstrated that HIV-1 uses a very efficient specific and common mechanism for virus cell-to-cell transfer from infected T cells and dissemination in macrophages, DCs and OCs by a two-step cell-fusion process leading to the formation of highly virus-productive multinucleated giant cells (MGCs) (Bracq, 2017; Raynaud-Messina, 2018; Xie, 2019, submitted), as evidenced in vivo tissues of HIV-1-infected patients. Infected T cells first establish contacts and fuse with macrophages or DC targets, and the newly formed fused cells then acquire the ability to fuse with surrounding non-infected DCs or macrophages leading to the formation of infected MGCs.

The group

• Serge Benichou: Team leader, Director, CNRS.
• Lucie Bracq: Post-doctoral fellow, Chinese Academy of Sciences.
• Héloise Leroy: PhD student, University Paris-Descartes.
• Maorong Xie: PhD student, University Paris-Descartes, China Scholarship Council.
• Mingyu Han, PhD student, University of Paris-Descartes, China Scholarship Council.
• Solène Cottis: Master student, University Paris-Pierre et Marie Curie.
• Léna Kleij, Master student, University Paris-Diderot.

Research interests

Since DC and macrophage myeloid cells are emerging as important cell targets of HIV-1, the general goal of our projects is to characterize, at the cellular and molecular levels, the cellular and viral mechanisms involved in HIV-1 cell-to-cell transfer and dissemination of these myeloid cells.

Our project is focused on 2 main specific objectives:

1-Characterization of the cellular and molecular mechanisms involved in virus cell-to-cell transfer and dissemination in myeloid cells. This objective will be focused on the analysis of the cellular signaling proteins and pathways (cystoskeleton organization, and cell surface proteins and pathways regulating cell-fusion of myeloid cells) that can be involved in the cell-fusion processes for virus spreading in macrophages and DCs.

2-Characterization of the role of host cell restriction factors counteracted by viral auxiliary proteins (Nef, Vpr, Vif, Vpu and Vpx) for cell-to-cell productive infection of myeloid cells. This second objective will determine whether and how HIV-1 cell-to-cell spreading in myeloid cells could overcome and/or bypass the inhibition imposed by anti-HIV-1 restriction factors.
Because all the data reported so far on HIV-1 infection of myeloid cells have been obtained through infection by cell-free viruses, characterization of the processes of cell-to-cell viral transfer from infected T cells toward these myeloid cells will give access to crucial information for AIDS pathogenesis, including i) HIV-1 sexual transmission, ii) HIV-1 spreading between cell targets in host tissues, and iii) establishment of persistent viral tissue reservoirs.

Publications marquantes et brevets

• Bracq, L., Xie, M., Benichou, S., and Bouchet, J. (2018) Mechanisms for cell-to-cell transmission of HIV-1. Front. Immunol., 9, 260.
• Raynaud-Messina, B., Bracq, L., Dupont, M., Souriant, S., Usmani, S. Proag, A., Pingris, K., Soldan, V., Thibault, C., Capilla, F., Al Saati, T., Gennero, I., Jurdic, P., Jolicoeur, P., Daviginon, J.-L., Mempel, T. Benichou, S., Maridonneau-Parini, I. and Verollet, C. (2018) The bone degradation machinery of osteoclasts: a novel HIV-1 target that contributes to bone loss. Proc. Natl. Acad. Sci. USA, 115(11), E2556-E2565.
• Bracq, L., Xie, M., Lambelé, M., Vu, L.-T., Matz, J., Schmitt, A., Delon, J., Zhou, P., Randriamampita, C., Bouchet, J., and Benichou, S. (2017). T cell-macrophage fusion triggers multinucleated giant cell formation for HIV-1 spreading. J. Virol., 91, e01237-17.
• Liu, L., Wang, W., Matz, J., Ye, C., Bracq, L., Delon, J., Kimata, J., Chen, Z., Benichou, S.* and Zhou, P.* (2016) Glycosyl Phosphatidylinositol-Anchored Variable Region of Llama Heavy Chain Only Antibody JM4 Efficiently Blocks Both Cell-Free and T Cell-T Cell Transmission of Human Immunodeficiency Virus Type 1. J. Virol., 90, 10642-10659. (*equal contribution)
• Herate, C., Vigne, C., Guenzel, C.A., Lambele, M., Rouyez, M.C., and Benichou S. (2016) Uracil DNA glycosylase interacts with the p32 subunit of the replication protein A complex to modulate HIV-1 reverse transcription for optimal virus dissemination. Retrovirology, 13, e26. 

Financial supports

This program is supported in part by Inserm, CNRS, and the University Paris-Descartes. It is funded by grants from ANRS, the French National Agency for AIDS Research, Sidaction, the Chinese Academy of Sciences (PIFI Program), and the China Scholarship Council (CSC).

Our research is conducted within the context of the Associated International Laboratory (LIA VirHost) supported by CNRS, Institut Pasteur, Université Paris-Descartes, Inserm and Institut Pasteur Shanghai-Chinese Academy of Sciences.