Autophagy is a fundamental cellular process that degrades or recycles intracellular components to maintain homeostasis and respond to stress, including infections. It is driven by a set of proteins known as ATG proteins, including the ATG8 family (LC3 and GABARAP proteins). Beyond their role in autophagy, ATG8 proteins are also involved in membrane trafficking, vesicle secretion, immune responses, and can be manipulated by viruses to support their replication.
HIV-1, the virus responsible for AIDS, assembles new viral particles in infected cells by recruiting its structural proteins (such as Gag) and its RNA genome at the cell membrane. Proper genome packaging is essential: without it, the virus cannot form infectious particles or spread efficiently.
While viral components required for genome packaging have been studied extensively, the role of cellular proteins in this process remained largely unexplored.
To address this, the research team used an unbiased mass spectrometry approach to determine the protein composition of HIV-1 particles and identify cellular factors involved in their assembly. The analysis revealed that HIV-1 particles are enriched in ATG8 proteins, particularly several members of the GABARAP family.
By combining proteomics, CRISPR-Cas9 genome editing, RNA-binding assays, and live-cell imaging, the researchers demonstrated that three ATG8 proteins — including GABARAPL1 — are incorporated into HIV-1 particles.
When GABARAP proteins are absent, the virus still produces particles, but they lose their infectivity. This defect results from a failure to package the viral RNA genome correctly. Instead of being transported to budding sites at the plasma membrane, the viral RNA accumulates in the cytoplasm alongside Gag proteins. The team also showed that GABARAPL1 directly binds viral RNA and interacts with Gag, confirming its active role in genome sorting.
These findings reveal a new function for GABARAP proteins — independent of classical autophagy — as cellular adaptors that enable HIV-1 genome packaging and the production of infectious viral particles. By redirecting these proteins to its advantage, HIV-1 ensures its infectivity and efficient dissemination.
This work was financially supported by ANRS, FRM, and SIDACTION.
Reference
Palaric M, Versapuech M, Judith D, Aubé C, Leduc M, Dutrieux J, Gautier EF, Paillart JC, Gallois-Montbrun S, Berlioz-Torrent C. GABARAP proteins regulate the packaging of HIV-1 genomic RNA into virions. EMBO Rep. 2025 Oct 31. doi: 10.1038/s44319-025-00607-1. Epub ahead of print. PMID: 41174262.
