Journal Article

CG dinucleotide suppression enables antiviral defence targeting non-self RNA

Gonçalves-Carneiro, Daniel, Takata, Matthew A., Bieniasz, Paul D., Soll, Steven J., Blanco-Melo, Daniel, Zang, Trinity M., York, Ashley

2017

Overview

Vertebrate genomes contain fewer CG dinucleotides than would be expected by chance, and this pattern is mimicked by many viruses; HIV-1 derivatives mutated to contain more CG dinucleotides are targeted by the human antiviral protein ZAP, suggesting that CG suppression has evolved in viruses to evade recognition. Viruses evade the ZAP Many virus genomes possess lower than expected numbers of 5′-CG-3′ dinucleotides, mimicking the CG suppression of their vertebrate hosts. The reason for this has been unclear, but Paul Bieniasz and colleagues now show that viruses use CG suppression to avoid recognition by the zinc-finger antiviral protein ZAP. They show that CG suppression is essential for HIV-1 replication; otherwise, the virus genome is recognized by ZAP and targeted for degradation. Vertebrate genomes exhibit marked CG suppression—that is, lower than expected numbers of 5′-CG-3′ dinucleotides 1 . 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 hosts 2 , 3 , 4 . This property of viral genomes is unexplained 4 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14 / 14/33 / 14/63 / 38 / 38/15 / 38/61 / 631/250/262/2106 / 631/326/596/1787 / 64/60 / Antiviral drugs / Cell Line / Crosslinking / Cytoplasm - genetics / Cytoplasm - virology / Cytosine / Deamination / Deoxyribonucleic acid / Dinucleoside Phosphates - genetics / DNA / GC Rich Sequence - genetics / Gene sequencing / Genetic aspects / Genomes / Health aspects / HIV / HIV-1 - genetics / HIV-1 - growth & development / HIV-1 - immunology / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Immunoprecipitation / Influenza / letter / multidisciplinary / Mutagenesis / Mutation / Nucleotide sequence / Nucleotides / Plasmids / Protein Binding / Proteins / Replication / Ribonucleic acid / RNA / RNA viruses / RNA, Viral - genetics / RNA, Viral - immunology / RNA, Viral - metabolism / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Science / Substrates / Vertebrates / Virions / Virus replication / Virus Replication - genetics / Viruses / Zinc finger proteins