Serge Benichou

Myeloid cells, especially macrophages, but also dendritic cells (DCs) and osteoclasts (OCs), are emerging as important target cells of HIV-1 and SARS-CoV-2 playing a major role in the pathogenesis of AIDS and COVID-19, respectively. While infection of myeloid cells by free viruses is highly inefficient, intercellular transfer of HIV-1 and SARS-CoV-2 may represent the dominant mode of dissemination of these viruses in vivo and allow productive infection of these target cells. The intercellular spread of these viruses could not only facilitate rapid viral dissemination between target cells but also promote escape from the immune response and contribute to the pathogenesis of these infections.

The general objective of our projects is to characterize the mechanisms involved in the intercellular dissemination of HIV-1 and SARS-CoV-2 in macrophages, as well as the consequences of this viral transfer on macrophage functions.

Our projects focus on two main objectives:
1- We have already demonstrated that HIV-1 uses a very efficient mechanism for the intercellular dissemination of the virus from infected T cells to macrophages, DCs and Ocs, through a 2-step cell-cell fusion process leading to the formation of multinucleated giant cells. We are currently characterizing i) the cellular factors and signaling pathways modulating the intercellular spread of the virus from infected T cells by cell fusion with macrophages; and ii) determining whether intercellular spread of HIV-1 in myeloid cells could overcome and/or bypass the inhibition imposed by anti-HIV-1 restriction factors counteracted by viral helper proteins (Nef, Vpr, Vif, Vpu and Vpx).
2- We want to determine if SARS-CoV-2 can also disseminate by cell-cell fusion between its different target cells, especially lung epithelial cells and macrophages. The objectives of this project are to study whether SARS-CoV-2 can trigger cell-cell fusion for viral transfer i) between infected and uninfected lung epithelial cells; ii) between infected and uninfected macrophages; and finally, iii) by cell-cell fusion between infected epithelial cells and target macrophages. The results obtained should provide insights into the role played by these multinucleated giant cells in viral dissemination, in immune and inflammatory responses, and in the spread of the virus to other organs.