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Post-transcriptional regulation of human immunodeficiency virus type-2 (HIV-2) replication by N6-methyladenosine

ABSTRACT: Human immunodeficiency virus type-2 (HIV-2) establishes reservoirs at levels comparable to HIV-1, but its infection is associated with lower rates of progression to AIDS. As such, a hallmark of people living with HIV-2 is the very low—usually undetectable—viral loads, which is partially explained by a post-transcriptional repression exerted at the level of protein synthesis and the accumulation of the full-length RNA in cytoplasmic granules. Here, we investigated whether HIV-2 Gag expression was regulated by the presence of the m6A RNA modification. Our results indicate that the HIV-2 full-length RNA contains m6A residues, which are required for Gag synthesis. Interestingly, the YTHDF family of cytoplasmic m6A readers exert different effects on HIV-2 Gag synthesis. As such, while YTHDF1 and YTHDF2 are necessary for Gag synthesis, YTHDF3 negatively regulates Gag expression by promoting full-length RNA localization in cytoplasmic granules. Interestingly, we demonstrate that the cellular m6A machinery including writers, erasers and readers re-localize into cytoplasmic granules together with the full-length RNA in a non-Gag producing cell sub-population. We also observed that FTO overexpression has no effect in Gag synthesis but promotes full-length RNA packaging suggesting a dynamic regulation of the cytoplasmic fate of this viral RNA. Together, these data suggest that the HIV-2 full-length RNA undergoes a complex regulation exerted by the cellular m6A machinery that controls the cytoplasmic localization, ribosome association and particle incorporation of this viral RNA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169556 | GEO | 2024/12/15

REPOSITORIES: GEO

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