Competitive virus and host RNAs: the interplay of a hidden virus and host interaction

Abstract

During virus infection, viral RNAs and mRNAs function as blueprints for viral protein synthesis and possibly as pathogen-associated molecular patterns (PAMPs) in innate immunity. Here, considering recent research progress in microRNAs (miRNAs) and competitive endogenous RNAs (ceRNAs), we speculate that viral RNAs act as sponges and can sequester endogenous miRNAs within infected cells, thus cross-regulating the stability and translational efficiency of host mRNAs with shared miRNA response elements. This cross-talk and these reciprocal interactions between viral RNAs and host mRNAs are termed "competitive viral and host RNAs" (cvhRNAs). We further provide recent experimental evidence for the existence of cvhRNAs networks in hepatitis B virus (HBV), as well as Herpesvirus saimiri (HVS), lytic murine cytomegalovirus (MCMV) and human cytomegalovirus (HCMV) infections. In addition, the cvhRNA hypothesis also predicts possible cross-regulation between host and other viruses, such as hepatitis C virus (HCV), HIV, influenza virus, human papillomaviruses (HPV). Since the interaction between miRNAs and viral RNAs also inevitably leads to repression of viral RNA function, we speculate that virus may evolve either to employ cvhRNA networks or to avoid miRNA targeting for optimal fitness within the host. CvhRNA networks may therefore play a fundamental role in the regulation of viral replication, infection establishment, and viral pathogenesis.

Figure 1

Inference of cvhRNA cross-regulation through miRNA response elements. (A) MiRNAs guide the recognition of target mRNAs through imperfect matches with their targeting sites and thus regulate the expression of target mRNAs at the post-transcriptional level. Each miRNA has multiple (up to tens) mRNA targets. Conversely, each mRNA may harbor multiple miRNA targeting sites (Ala et al., 2013). (B) Viral RNAs and mRNAs harboring miRNA response elements exert their suppression of miRNA as sponges. Host mRNAs may act in a similar way. Thus, viral RNAs and host mRNAs could competitively sequester the same miRNA pool within infected cells. Viral RNAs as miRNA sponges can de-repress the miRNA-mediated inhibition of host mRNAs. Therefore, a cross-regulation may be formed between viral RNAs and host mRNAs that share common miRNA response elements. Stimulation (↑) or inhibition (┬) is determined following how miRNAs or RNAs impact the activities of RNAs or miRNAs

Figure 2

Schematic figure of how cvhRNA networks may mediate viral replication, infection, and the development of HCC during HBV infection. In hepatocytes, miR-122 effectively suppresses the expression of its target genes (cyclin G1, PBF, and NT5C3) at the post-transcriptional level by binding to the miRNA response element within the 3′-UTR of target mRNAs. During HBV infection, high levels of viral RNAs harboring a miR-122 response element in their 3′-UTR competitively sponge and efficiently sequester cellular miR-122, thus blocking the binding of miR-122 to its host target mRNAs. In this manner, viral RNAs de-repress and rescue the expression of host target mRNAs. Similarly, HBV RNAs positively cross-regulate Bcl-2 expression through shared miR-15a/16 response elements. The dose effect between competitive HBV RNAs and host mRNAs is shown. In the networks consisting of four viral RNAs (pgRNA, pre-S, S, and X mRNAs) and four host mRNAs (cyclin G1, PBF, NT5C3, and Bcl-2), elevated expression of de-repressed host genes contributes to enhanced HBV replication, persistent viral infection, and HCC development

Figure 3

Potential alteration of host mRNA homeostasis by viral RNAs. Many mammalian viruses produce high levels of redundant viral RNAs and mRNAs. According to the cvhRNAs hypothesis, under certain conditions for cvhRNA activity in viral infections, these viral RNAs could modify the balance between cellular miRNAs and host mRNA targets in a miRNA response sequence dependent and coding independent manner. Viral RNAs directly result in the depression of cellular transcripts with shared miRNA response elements and the subsequent aberrant expression of host proteins