Thèse la Reprogrammation de la Dynamique Membranaire de l'Hôte Comme Stratégie Antivirale H/F - Doctorat.Gouv.Fr

Établissement : Université de Toulouse École doctorale : BSB - Biologie, Santé, Biotechnologies Laboratoire de recherche : IPBS - Institut de Pharmacologie et Biologie Structurale Direction de la thèse : Fabrice DUMAS ORCID 0000000291644527 Début de la thèse : 2027-09-01 Date limite de candidature : 2026-11-23T23:59:59 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.
Co-infection with Mycobacterium tuberculosis (Mtb) and HIV-1 is one of the leading causes of infectious disease-related mortality worldwide. While HIV-induced CD4 T-cell depletion promotes the progression of tuberculosis, the reverse is also true: tuberculosis infection enhances HIV-1 replication and dissemination through mechanisms that remain poorly understood.

Macrophages are at the heart of this interplay, as they represent common target cells for both pathogens. They can act as long-term viral reservoirs, harbor viral particles within specialized virus-containing compartments (VCCs), and support highly efficient cell-to-cell viral transmission through direct cell contacts involving virological synapses and tunneling nanotubes (TNTs). Our team has demonstrated that a TB-associated inflammatory microenvironment promotes TNT formation and enhances HIV-1 transfer between macrophages (Cell Reports, 2019).

In parallel, Membrane Lipid Therapy (MLT) is an emerging approach based on the ability to modulate the physical properties and organization of cellular membranes to regulate biological functions. Although this strategy has shown therapeutic potential in several diseases, its antiviral potential remains largely unexplored. Our preliminary data show that several polyunsaturated fatty acid derivatives (D-PUFAs) efficiently inhibit HIV-1 infection, suggesting that membrane remodeling could represent a novel host-directed therapeutic strategy. The overall objective of this project is to determine whether lipid derivatives capable of remodeling plasma membrane properties can inhibit HIV-1 persistence and cell-to-cell transmission between macrophages.

Plus spécifiquement, le projet s'articule autour de trois objectifs :

- Évaluer l'activité antivirale de dérivés lipidiques sur l'infection des macrophages, la formation des compartiments contenant les virus (VCCs), le transfert intercellulaire du VIH-1 et la formation de cellules géantes multinucléées.
- Identifier les mécanismes membranaires responsables de cette activité en analysant les modifications de la composition lipidique, de l'organisation des nanodomaines, de la dynamique des récepteurs et des propriétés biophysiques de la membrane.
- Déterminer l'impact des dérivés lipidiques sur les nanotubes de tunneling (TNTs), structures impliquées dans la dissémination virale entre macrophages, et évaluer leur potentiel pour limiter la propagation du virus dans un contexte inflammatoire mimant la co-infection VIH/TB. The project will combine complementary approaches in virology, membrane biophysics, and advanced imaging:

Cellular models: primary human macrophages and in vitro models of HIV/TB co-infection.
Virology: HIV-1 infection, quantification of viral replication, analysis of cell-to-cell viral transfer, and macrophage fusion.
Membrane biology: treatment with lipid derivatives, quantitative lipidomics by mass spectrometry, and analysis of membrane lipid composition.
Imaging: confocal microscopy, super-resolution microscopy, and cryo-electron microscopy to characterize virus-containing compartments (VCCs), tunneling nanotubes (TNTs), and viral trafficking.

We are seeking a highly motivated candidate holding a Master's degree (MSc or equivalent) in Biology, with a background in virology, immunology, cell biology, biophysics, or a related field.

Desired scientific skills
- Strong knowledge of cell and molecular biology.
- Good understanding of virology and/or immunology.
- Hands-on experience in mammalian cell culture and standard laboratory techniques.
Experience in fluorescence or confocal microscopy, membrane biology, or quantitative image analysis will be considered an advantage.
Basic skills in statistical analysis and data processing (GraphPad Prism, ImageJ/Fiji, or equivalent software) are desirable.

Personal qualities
Ability to collaborate effectively within a multidisciplinary and international research environment.
Good command of spoken and written scientific English.

Application link: https://edd-projets.utoulouse.fr/

• Gestion des données
• Anglais
• ImageJ