The <scp>EBNA</scp> ‐1 Conundrum: Does Epstein–Barr Virus Invoke Autoimmune Pathology in a Population Subset by Poorly Purine‐Loading Its Major Latency‐Maintaining Transcript?

Viruses activate host defences by alerting interferon and other alarms. Viruses seeking latency must curtail this. Infected subjects would then have minimal immune system activation and remain healthy. However, a minority cannot prevent emergence of associated diseases. This conundrum remains despite our understanding (i) that interferon specifically suppresses the translation of viral mRNAs, but not host mRNAs, and (ii) that for the latent state only one latency-maintaining mRNA may be needed. Critical are mRNA loadings with purine (R) bases, relative to pyrimidine bases (Y). Base composition and structural studies have established the genome-wide potential of duplex DNA (hence transcripts thereof) to extruded stem-loops, the stems of which require parity between R and Y bases. Sometimes conflicting with coding demands, parity-violations (R > Y) decrease this potential in exons (and hence in mRNAs). Thus, one mRNA (EBNA-1) of the Epstein-Barr virus (EBV) is successful in not alerting hosts to immune awareness. However, Y-rich transcripts might occasionally arise in the highly polymorphic 'junk DNA', long known as pervasively transcribed. Thus, within a minor subset of the infected population, some may, by chance, have randomly mutated to create pyrimidine-loaded regions that would form forbidden double-stranded RNA duplexes with purine-loaded EBNA-1 mRNAs. Thus, immune systems would awaken. Other viruses, differing in types/extents of latency, have evolved different survival strategies. Thus, mRNAs of the extremely latent human T cell leukaemia virus (HTLV1) are Y-loaded (Y > R), but a single latency transcript is highly R-loaded. In contrast, most mRNAs of less extremely latent retrovirus (HIV1) are expressed with R > Y.