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Single-molecule epitranscriptomic analysis of full-length HIV-1 RNAs reveals functional roles of site-specific m 6 As
Journal article   Open access   Peer reviewed

Single-molecule epitranscriptomic analysis of full-length HIV-1 RNAs reveals functional roles of site-specific m 6 As

Alice Baek, Ga-Eun Lee, Sarah Golconda, Asif Rayhan, Anastasios A Manganaris, Shuliang Chen, Nagaraja Tirumuru, Hannah Yu, Shihyoung Kim, Christopher Kimmel, …
Nature microbiology, Vol.9(5), pp.1340-1355
04/11/2024
DOI: 10.1038/s41564-024-01638-5
PMCID: PMC11087264
PMID: 38605174
url
https://doi.org/10.1038/s41564-024-01638-5View
Published (Version of record) Open Access

Abstract

Although the significance of chemical modifications on RNA is acknowledged, the evolutionary benefits and specific roles in human immunodeficiency virus (HIV-1) replication remain elusive. Most studies have provided only population-averaged values of modifications for fragmented RNAs at low resolution and have relied on indirect analyses of phenotypic effects by perturbing host effectors. Here we analysed chemical modifications on HIV-1 RNAs at the full-length, single RNA level and nucleotide resolution using direct RNA sequencing methods. Our data reveal an unexpectedly simple HIV-1 modification landscape, highlighting three predominant N -methyladenosine (m A) modifications near the 3' end. More densely installed in spliced viral messenger RNAs than in genomic RNAs, these m As play a crucial role in maintaining normal levels of HIV-1 RNA splicing and translation. HIV-1 generates diverse RNA subspecies with distinct m A ensembles, and maintaining multiple of these m As on its RNAs provides additional stability and resilience to HIV-1 replication, suggesting an unexplored viral RNA-level evolutionary strategy.

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