La reprogrammation de la dynamique membranaire de l'hôte comme stratégie antivirale

Co-infection with Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), and HIV-1 remains a major global health challenge. Beyond the well-established HIV-1-induced depletion of CD4⁺ T cells that promotes TB progression, increasing evidence indicates that Mtb also enhances HIV-1 replication and dissemination through mechanisms that are still poorly understood. Macrophages, which are common target cells for both pathogens, occupy a central position in this interplay: they sustain productive HIV-1 infection, promote cell-to-cell viral transmission, and sequester viral particles within virus-containing compartments (VCCs), thereby providing a protected niche for viral persistence. Moreover, interactions between macrophages and infected CD4⁺ T cells facilitate viral dissemination through specialized membrane and actin-based structures, including tunneling nanotubes (TNTs) and virological synapses. In this context, we demonstrated that a TB-associated inflammatory microenvironment induces TNT formation in macrophages, enhancing both intercellular HIV-1 transfer and viral production, and we proposed that this mechanism contributes to the elevated viral load observed in HIV/TB co-infected patients (Souriant et al., Cell Reports, 2019).Together, these findings identify plasma membrane organization, receptor dynamics, and membrane–cytoskeleton interactions as key regulators of HIV-1 persistence and spread, making the macrophage membrane an attractive target for host-directed antiviral therapies. Membrane lipid therapy (MLT) is an innovative therapeutic approach that exploits the ability of lipids, particularly polyunsaturated fatty acids (PUFAs), to modulate cell signaling and immune responses. Several studies have demonstrated the potential of MLTs for the treatment of cancer, metabolic, cardiovascular, and neurodegenerative diseases. While viruses such as HIV-1 exploit membrane dynamics to enter, infect, and persist in host cells, the therapeutic potential of MLTs and membrane lipids has yet to be investigated in the context of infectious diseases. In this context, our team has established a collaboration with Dr. Escribá's group (Spain), which pioneered MLT, to investigate this innovative therapeutic strategy in the context of HIV-1 infection. Our preliminary data show that some D-PUFAs inhibit HIV-1 infection in a cell-type-specific manner. These findings suggest that MLT compounds may inhibit HIV-1 infection by remodeling host cell membranes and provide a strong rationale for elucidating the underlying molecular mechanisms, with a particular focus on their effects in macrophages. This project will determine whether membrane-active lipid derivatives can inhibit HIV-1 persistence and cell-to-cell dissemination between macrophages by remodeling plasma membrane organization and membrane–cytoskeleton interactions, particularly in the context of HIV/TB co-infection. This project will be developed in collaboration with Dr Neyrolle's team in Toulouse and with Luciana Balboa (Argentina) that will co-supervise the PhD. École doctorale : BSB - Biologie, Santé, Biotechnologies Direction : Fabrice DUMAS Financement : MSCA COFUND BEST