2025-09-18 フランス国立科学研究センター(CNRS)
<関連情報>
- https://www.cnrs.fr/en/press/tuberculosis-vulnerability-people-hiv-viral-protein-implicated
- https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1013183
HIV-1 Tatはクラトリン依存性エンドサイトーシスとオートファジーを阻害することで結核菌およびトキソプラズマの増殖を促進する HIV-1 Tat favors the multiplication of Mycobacterium tuberculosis and Toxoplasma by inhibiting clathrin-mediated endocytosis and autophagy
Aurélie Rivault,Audrey Bernut,Myriam Ben-Neji,Magali Abrantes,Maxime Jansen,Sylvaine Huc-Brandt,Sébastien Besteiro,Yann Bordat,Mai Nguyen-Chi,Nelly Audemard,Margaux Mesleard-Roux,David Perrais,Olivier Neyrolles, [ … ],Bruno Beaumelle
PLOS Pathogens Published: September 11, 2025
DOI:https://doi.org/10.1371/journal.ppat.1013183
Abstract
HIV-1 and Mycobacterium tuberculosis (Mtb) coinfections are a major public health problem but are not well characterized. HIV-1 Tat is secreted by infected cells, generating nanomolar concentrations of Tat in the sera of people living with HIV. Circulating Tat enters cells, binds to PI(4,5)P2 then undergoes palmitoylation, thereby becoming resident on this phosphoinositide. Here, we found that Tat favors the multiplication of Mtb in macrophages. Moreover, Tat renders zebrafish larvae more sensitive to mycobacterial infection. We found that Tat binding to PI(4,5)P2 and palmitoylation enable Tat to inhibit the recruitment of the AP-2 adaptor, thereby inhibiting clathrin-mediated endocytosis and in turn autophagy. This inhibition prevents the degradation of intracellular pathogens such as Mtb and opsonized Toxoplasma gondii, but also of lipid droplets, thereby facilitating the access of these pathogens to lipids. We thus identified a mechanism enabling HIV Tat to favor the multiplication of intracellular pathogens such as Mtb.
Author summary
HIV-1 and Mycobacterium tuberculosis (Mtb) coinfections are a major public health problem but are not well understood. The HIV-1 Tat protein is efficiently secreted by infected T-cells, generating nanomolar concentrations of Tat in the sera of people living with HIV, even treated with antiretroviral therapy. Circulating Tat enters cells, reaches the cytosol, binds to the inner leaflet of the plasma membrane and is modified by a fatty acid, thereby becoming resident on the cell membrane. Here, we found that Tat favors the multiplication of Mtb in macrophages, that are the main Mtb target. We also found that Tat sensitized zebrafish larvae to mycobacterial infection and increased the number of granulomas, that are infection foci observed in vivo. We found that Tat binding to a specific lipid and its modification by a fatty acid enable Tat to inhibit endocytosis and in turn autophagy, which is a process enabling the cell to fight intracellular pathogens. This inhibition thus prevents the degradation of intracellular pathogens such as Mtb and Toxoplasma gondii, but also of intracellular lipid droplets, thereby facilitating the access of these pathogens to lipids. We thus identified a mechanism enabling HIV Tat to favor the multiplication of intracellular pathogens such as Mtb.
