Double-stranded RNA as a Not-self Alarm Signal: to Evade, most Viruses Purine-load their RNAs, but some (HTLV-1, Epstein-Barr) Pyrimidine-load

Abstract

For double-stranded RNA (dsRNA) to signal the presence of foreign (non-self) nucleic acid, self-RNA–self-RNA interactions should be minimized. Indeed, self-RNAs appear to have been fine-tuned over evolutionary time by the introduction of purines in clusters in the loop regions of stem-loop structures. This adaptation should militate against the “kissing” interactions which initiate formation of dsRNA. Our analyses of virus base compositions suggest that, to avoid triggering the host cell's dsRNA surveillance mechanism, most viruses purine-load their RNAs to resemble host RNAs (“stealth” strategy). However, some GC-rich latent viruses (HTLV-1, EBV) pyrimidine-load their RNAs. It is suggested that when virus production begins, these RNAs suddenly increase in concentration and impair host mRNA function by virtue of an excess of complementary “kissing” interactions (“surprise” strategy). Remarkably, the only mRNA expressed in the most fundamental form of EBV latency (the “EBNA-1 program”) is purine-loaded. This apparent stealth strategy is reinforced by a simple sequence repeat which prefers purine-rich codons. During latent infection the EBNA-1 protein may evade recognition by cytotoxic T-cells, not by virtue of containing a simple sequence amino acid repeat as has been proposed, but by virtue of the encoding mRNA being purine-loaded to prevent interactions with host RNAs of either genic or non-genic origin.