Letter | Published:

CG dinucleotide suppression enables antiviral defence targeting non-self RNA

Nature volume 550, pages 124127 (05 October 2017) | Download Citation


Vertebrate genomes exhibit marked CG suppression—that is, lower than expected numbers of 5′-CG-3′ dinucleotides1. This feature is likely to be due to C-to-T mutations that have accumulated over hundreds of millions of years, driven by CG-specific DNA methyl transferases and spontaneous methyl-cytosine deamination. Many RNA viruses of vertebrates that are not substrates for DNA methyl transferases mimic the CG suppression of their hosts2,3,4. This property of viral genomes is unexplained4,5,6. Here we show, using synonymous mutagenesis, that CG suppression is essential for HIV-1 replication. The deleterious effect of CG dinucleotides on HIV-1 replication was cumulative, associated with cytoplasmic RNA depletion, and was exerted by CG dinucleotides in both translated and non-translated exonic RNA sequences. A focused screen using small inhibitory RNAs revealed that zinc-finger antiviral protein (ZAP)7 inhibited virion production by cells infected with CG-enriched HIV-1. Crucially, HIV-1 mutants containing segments whose CG content mimicked random nucleotide sequence were defective in unmanipulated cells, but replicated normally in ZAP-deficient cells. Crosslinking–immunoprecipitation–sequencing assays demonstrated that ZAP binds directly and selectively to RNA sequences containing CG dinucleotides. These findings suggest that ZAP exploits host CG suppression to identify non-self RNA. The dinucleotide composition of HIV-1, and perhaps other RNA viruses, appears to have adapted to evade this host defence.

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We thank T. Kueck for primary lymphocytes and S. Giese for assistance with smFISH. This work was supported NIH grants R01AI50111 and P50GM103297 (to P.D.B.)

Author information


  1. Laboratory of Retrovirology, The Rockefeller University, New York, New York, USA

    • Matthew A. Takata
    • , Daniel Gonçalves-Carneiro
    • , Trinity M. Zang
    • , Steven J. Soll
    • , Ashley York
    • , Daniel Blanco-Melo
    •  & Paul D. Bieniasz
  2. Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA

    • Trinity M. Zang
    • , Steven J. Soll
    •  & Paul D. Bieniasz


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M.A.T. performed all experiments unless otherwise stated and wrote the paper. D.G.-C. performed some of the luciferase reporter experiments and bioinformatic analyses. T.M.Z. performed smFISH experiments. A.Y. performed some of the CLIP experiments. D.B.-M. generated the mutant sequence in silico. S.J.S. constructed and characterized the 16 original mutant HIV-1 strains. P.D.B. conceived the study, supervised the work and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul D. Bieniasz.

Reviewer Information Nature thanks G. Towers and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data

Supplementary information

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    Supplementary Information

    This file contains uncropped Western blots used in Figures 2 and 3, and in Extended Data Figures 2, 5 and 6.

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    Reporting Summary

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    Supplementary Data 1

    A codon by codon list of the mutations made in segment L

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    Supplementary Data 2

    Alignment of WT and mutant EH segments (Fasta format).

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    Supplementary Data 3

    Alignment of WT and mutant L segments (Fasta format).

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