PT  - JOURNAL ARTICLE
AU  - Camila Pereira-Montecinos
AU  - Daniela Toro-Ascuy
AU  - Cecilia Rojas-Fuentes
AU  - Sebastián Riquelme-Barrios
AU  - Bárbara Rojas-Araya
AU  - Francisco García-de-Gracia
AU  - Paulina Aguilera-Cortés
AU  - Catarina Ananías-Sáez
AU  - Grégoire de Bisschop
AU  - Jonás Chaniderman
AU  - Mónica L. Acevedo
AU  - Bruno Sargueil
AU  - Fernando Valiente-Echeverría
AU  - Ricardo Soto-Rifo
TI  - An epitranscriptomic switch at the 5′-UTR controls genome selection during HIV-1 genomic RNA packaging
AID  - 10.1101/676031
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 676031
4099  - http://biorxiv.org/content/early/2019/06/19/676031.short
4100  - http://biorxiv.org/content/early/2019/06/19/676031.full
AB  - During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA (gRNA). While the simple retrovirus MLV segregates its full-length RNA into two functional populations, the HIV-1 full-length RNA was proposed to exist as a single population used indistinctly for protein synthesis or packaging. However, the mechanisms by which the HIV-1 Gag protein selects the two RNA molecules that will be packaged into nascent virions remain poorly understood. Here, we demonstrate that HIV-1 full-length RNA packaging is regulated through an epitranscriptomic switch requiring demethylation of two conserved adenosine residues present within the 5′-UTR. As such, while m6A deposition by METTL3/METTL14 onto the full-length RNA was associated with increased Gag synthesis and reduced packaging, FTO-mediated demethylation was required for the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and drives full-length RNA demethylation. Finally, the specific inhibition of the FTO RNA demethylase activity suppressed HIV-1 full-length RNA packaging. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the full-length RNA molecules that will be used as viral genomes.