Article

Dynamics of the human and viral m6A RNA methylomes during HIV-1 infection of T cells

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Abstract

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNA. Very little is known of the function of m6A in the immune system or its role in host–pathogen interactions. Here, we investigate the topology, dynamics and bidirectional influences of the viral–host RNA methylomes during HIV-1 infection of human CD4 T cells. We show that viral infection triggers a massive increase in m6A in both host and viral mRNAs. In HIV-1 mRNA, we identified 14 methylation peaks in coding and noncoding regions, splicing junctions and splicing regulatory sequences. We also identified a set of 56 human gene transcripts that were uniquely methylated in HIV-1-infected T cells and were enriched for functions in viral gene expression. The functional relevance of m6A for viral replication was demonstrated by silencing of the m6A writer or the eraser enzymes, which decreased or increased HIV-1 replication, respectively. Furthermore, methylation of two conserved adenosines in the stem loop II region of HIV-1 Rev response element (RRE) RNA enhanced binding of HIV-1 Rev protein to the RRE in vivo and influenced nuclear export of RNA. Our results identify a new mechanism for the control of HIV-1 replication and its interaction with the host immune system.

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Author information

Affiliations

  1. Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California 92093, USA

    • Gianluigi Lichinchi
    • , Shang Gao
    • , Vikas Bansal
    •  & Tariq M. Rana
  2. Program for RNA Biology and Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA

    • Gianluigi Lichinchi
    •  & Tariq M. Rana
  3. Department of Physiology and Biophysics and the Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University, 1305 York Avenue, New York, New York 10021, USA

    • Yogesh Saletore
    •  & Christopher E. Mason
  4. Environmental Toxicology Graduate Program and Department of Chemistry, University of California, Riverside, California 92521, USA

    • Gwendolyn Michelle Gonzalez
    •  & Yinsheng Wang
  5. The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, The Feil Family Brain and Mind Research Institute (BMRI), New York, New York, 10021, USA

    • Christopher E. Mason
  6. Institute for Genomic Medicine and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA

    • Tariq M. Rana

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Contributions

G.L. designed and performed experiments, analysed data and wrote the paper. S.G. performed experiments and analysed data. Y.S. performed experiments and analysed data. G.M.G. performed experiments and analysed data. V.B., Y.W. and C.M. analysed data. T.M.R. contributed to the concept and design, data analysis and manuscript writing.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tariq M. Rana.

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    Supplementary Information

    Supplementary Methods, Figures 1–6 and Tables 1–4.