Epitranscriptomic regulation of HIV-1 full-length RNA packaging

During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA. 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 deposition of N-6-methyladenosine (m(6)A) regulates full-length RNA packaging. While m(6)A deposition by METTL3/METTL14 onto the full-length RNA was associated with increased Gag synthesis and reduced packaging, FTO-mediated demethylation promoted the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and contributes to full-length RNA demethylation. We further identified two highly conserved adenosines within the 5 '-UTR that have a crucial functional role in m(6)A methylation and packaging of the full-length RNA. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the HIV-1 full-length RNA molecules that will be used as viral genomes.

Automated summary

This study reveals the regulatory role of N-6-methyladenosine (m(6)A) deposition on HIV-1 full-length RNA packaging, as well as the interaction between HIV-1 Gag protein and RNA demethylase FTO. The results show that m(6)A deposition leads to increased Gag synthesis and reduced packaging, while FTO-mediated demethylation promotes the incorporation of the full-length RNA into viral particles.