ATG5 protein is a central mediator of a non-canonical autophagy pathway hijacked by HIV-1 to weaken the host's response to infection

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VIH (orange) à la surface d'une cellule infectée (vert) Crédits : Philippe Roingeard, Camille Marchand

Understanding how viruses overcome the host's innate defenses to efficiently spread is crucial in the fight against infections. Scientists from the "Host-Virus Interactions" team, are studying "restriction factors", cellular factors that block the replication cycle of viruses, and the viral countermeasure in response to these intrinsic "roadblocks". In a new study, these scientists have discovered a cellular pathway that is exploited by the HIV-1 virus (human immunodeficiency virus type 1) to overcome a viral restriction factor called BST2/Tetherin. Their findings have been published in the PNAS journal in May 2023.

With over 650,000 deaths attributed to this infection in 2021, HIV-1, the virus that causes AIDS, remains a major global public health issue. To combat the spread of HIV-1, the host has developed an arsenal of immune defenses, including intrinsic cellular defenses that involve interactions between viral and cellular proteins. Host restriction factors, a set of proteins with direct or indirect antiviral activity, are an important facet of this intrinsic defense against the virus. BST2/Tetherin is one mediator of this innate immunity and exerts its antiviral activity on many enveloped viruses. This restriction factor physically retains newly formed viruses on the surface of infected cells, preventing their release and further dissemination. BST2/Tetherin is also a sensor of infection, and its activation puts the cell in an antiviral state.

Faced with these restrictions, lentiviruses, including HIV-1, have evolved and developed various strategies to counter these cellular barriers. Through protein-protein interactions involving viral accessory proteins, lentiviruses target restriction factors for degradation or sequester them in intracellular compartments. The Vpu protein of HIV-1 is one of the responses developed by the virus to counter the restriction factor BST2/Tetherin. Vpu reduces the amount of BST2 at the site of viral budding by diverting intracellular trafficking and degradation pathways. Previous work from the team highlighted that Vpu usurps a cellular degradation mechanism, similar to a non-canonical process of autophagy called LC3-associated phagocytosis, to counteract the activity of BST2 and allow efficient virus dissemination.

The recent findings from the "Host-Virus Interactions" team within Institut Cochin shed new light on the early stages of the non-canonical autophagy pathway that is hijacked by the HIV-1 virus to counteract the restriction factor BST2/Tetherin.

Through advanced microscopy and biochemical approaches, these scientists discovered that this process is initiated at the surface of infected cells by the recognition of specific forms of BST2 by an autophagic protein called ATG5. ATG5 binds to phosphorylated and dimerized BST2 molecules tethering viral particles on the cell surface, directing them towards this non-canonical autophagy pathway for degradation. Importantly, this function of ATG5 is separate from its role in canonical autophagy, which regulates cellular homeostasis. The team also showed that the viral protein Vpu's hijacking of this pathway attenuates the host's antiviral response, which is initiated when BST2 senses viruses.

Overall, this study reveals that ATG5 acts as a central mediator of this non-canonical autophagy pathway hijacked by the viral protein Vpu to weaken the host's response to infection.

BST2/Tetherin has a broad restriction activity against various enveloped viruses. These discoveries are likely to have implications for research on many enveloped viruses, or on extracellular elements trapped by BST2 at the surface of cells (such as exosomes or midbodies). Furthermore, the discovery of a new function of the protein ATG5, independent of autophagy, as an adapter for membrane receptors opens up new avenues for research on the contribution of ATG5 in engaging surface receptors in the non-canonical autophagy pathway.

This program is funded by SIDACTION and ANRS.


Judith D, Versapuech M, Bejjani F, Palaric M, Verlhac P, Kuster A, Lepont L, Gallois-Montbrun S, Janvier K, Berlioz-Torrent C. ATG5 selectively engages virus-tethered BST2/tetherin in an LC3C-associated pathway. Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2217451120. doi: 10.1073/pnas.2217451120. Epub 2023 May 8. PMID: 37155854.


Clarisse Berlioz

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