Myeloid cells, including macrophages but also dendritic cells (DCs) and osteoclasts (OCs) are emerging as import target cells of HIV-1 and SARS-CoV-2 playing critical roles in the pathogenesis of AIDS and COVID-19, respectively. Because these myeloid cells are poorly infected by cell-free viruses, cell-to-cell transfer of HIV-1 and SARS-CoV-2 may represent the dominant mode of virus dissemination in vivo and may allow for productive infection of these cell types. Virus cell-to-cell spread may not only facilitate rapid viral dissemination between the target cells but may also promote immune evasion and contribute to pathogenesis.
The general goal of our projects is to characterize the cellular and virological mechanisms involved in HIV-1 and SARS-CoV-2 cell-to-cell transfer and dissemination in macrophages and other myeloid cells, as well as the consequences of this virus transfer on macrophages functions.
Our projects are thus focused on 2 main objectives:
1- We have already demonstrated that HIV-1 uses a very efficient mechanism for virus cell-to-cell transfer from infected T cells and dissemination in macrophages, DCs and OCs by a two-step cell-cell fusion process leading to the formation of highly virus-productive multinucleated giant cells. We are now i) characterizing the cellular factors and signaling pathways modulating virus cell-to-cell dissemination from infected T cells through cell-cell fusion with macrophages; and ii) determining whether HIV-1 cell-to-cell spreading in myeloid cells could overcome and/or bypass the inhibition imposed by anti-HIV-1 restriction factors counteracted by the viral auxiliary proteins (Nef, Vpr, Vif, Vpu and Vpx).
2- We want to characterize whether SARS-CoV-2 could also mediate cell-cell fusion for virus cell-to-cell transfer and dissemination between its different target cells, including lung epithelial cells and myeloid cells, such as macrophages and monocytes. The aims of this project are to investigate whether SARS-CoV-2 can trigger cell-cell fusion for virus transfer i) between infected and non-infected lung epithelial cells; ii) between infected and non-infected myeloid cells; and finally, iii) through cell-cell fusion between infected epithelial cells and myeloid target cells. The results obtained should open avenues for further elucidation of the role played by these infected large multinucleated syncytia in viral spreading, in immune and inflammatory responses, as well as for virus dissemination in other tissues and organs.