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Inhibitors of Tax1-PDZ Interactions Block HTLV-1 Viral Transmission by Changing EV Composition
Jedidja Puttemans1, Yasmine Brammerloo1, Karim Blibek1
1Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute, University of Liege, Liège, Belgium.
Journal of Extracellular Vesicles
|August 6, 2025
Summary
Human T-cell leukemia virus type-1 (HTLV-1) uses extracellular vesicles (EVs) to spread. The viral Tax-1 protein interacts with human PDZ proteins, altering EV cargo. Inhibiting this interaction boosts antiviral factors in EVs, offering a potential therapeutic strategy.
Area of Science:
- Virology
- Cell Biology
- Structural Biology
Background:
- Extracellular vesicles (EVs) mediate the spread of enveloped RNA viruses, including Human T-cell leukemia virus type-1 (HTLV-1).
- The HTLV-1-encoded Tax-1 protein is found in EVs, but its role in EV cargo regulation is unclear.
- PDZ proteins are crucial regulators of EV formation and composition.
Purpose of the Study:
- To map interactions between HTLV-1 Tax-1 and human PDZ proteins.
- To understand the structural basis of Tax-1/PDZ interactions.
- To investigate the therapeutic potential of targeting Tax-1/PDZ interactions for HTLV-1 infection.
Main Methods:
- Generated a comprehensive interaction map between Tax-1 and human PDZome components.
- Performed nuclear magnetic resonance (NMR) spectroscopy to determine the structural basis of Tax-1/syntenin-1 interaction.
- Assessed the impact of a small molecule inhibitor on Tax-1/syntenin-1 interaction, EV cargo, and antiviral activity.
Main Results:
- Tax-1 interacts with over one-third of human PDZome proteins, including syntenin-1, a key regulator of EV biogenesis.
- The structural basis of Tax-1 interaction with syntenin-1 PDZ domains was elucidated.
- Inhibition of Tax-1/syntenin-1 interaction altered EV composition, increasing antiviral proteins and microRNAs (e.g., miR-320 family).
Conclusions:
- Tax-1 manipulates host PDZ proteins to influence EV cargo during HTLV-1 infection.
- Targeting the Tax-1/syntenin-1 interaction can reprogram EVs to carry antiviral factors.
- EV-encapsulated miR-320c mimics show potential as a therapeutic strategy against HTLV-1-induced diseases.
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