Opinion Viral Enhancer Mimicry of Host Innate-Immune Promoters

The inflammatory milieu is the natural habitat for a pathogenic infection, char-acterised by activity of pro-inflammatory signalling pathways and inflammatory cytokines. Viral entry rapidly activates a range of innate-immune signalling events such as the activation of Pattern Recogni-tion Receptors (PRRs) [1–5]. A virus must therefore counteract intrinsic cellular and innate-immune responses to successfully complete the replication cycle. Frequently this is accomplished by encoding viral effector molecules that block these cellular responses by working as either structural or functional mimics of host target pro-teins [6–11]. Nuclear DNA viruses are dependent on the host transcriptional machinery to express the first viral genes; for example the immediate-early (IE) control elements of DNA viruses are by definition absolutely dependent on host transcription factors (TF) [12]. Therefore, these viruses are particularly hostage to their host transcriptional environment [13,14]. Here we propose that mimicry of regulatory DNA sequences by viral regulatory regions may also provide an additional strategy to counteract at IE times of infection the innate-immune response. In this context, viral IE control elements might functionally mimic innate-immune enhancers, taking advantage of the activated immune signalling TFs for promoting viral IE gene expression. In other words: ‘‘If you can’t beat ‘em. Join ‘em.’’ In exploring this possibility, we present a synopsis of the promoter-regulatory elements from seven extensively studied mammalian viruses with a DNA stage, and seven promoters representing prototypical cellular innate-immune genes. These are the SV-40 early enhancer, the E1A enhancer of HAdV5, the long terminal repeat (LTR) of HIV-1, the E6/7 long control region (LCR) of both HPV-16 and HPV-18, the major IE (MIE) enhancer of HCMV, and the enhancer-1 (Eh-1) regu-latory region of HBV for viral sequences, and the enhancer regions of huma