Innate immune evasion strategies of DNA and RNA viruses

Abstract

Upon infection, both DNA and RNA viruses can be sensed by pattern recognition receptors (PRRs) in the cytoplasm or the nucleus to activate antiviral innate immunity. Sensing of viral products leads to the activation of a signaling cascade that ultimately results in transcriptional activation of type I and III interferons, as well as other antiviral genes that together mediate viral clearance and inhibit viral spread. Therefore, in order for viruses to replicate and spread efficiently, they must inhibit the host signaling pathways that induce the innate antiviral immune response. In this review, we will highlight recent advances in the understanding of the mechanisms by which viruses evade PRR detection, intermediate signaling molecule activation, transcription factor activation, and the actions of antiviral proteins.

Figure 1

Evasion of RIG-I-like receptor signaling by viruses. The RIG-I-like receptors RIG-I and MDA5 are activated by viral dsRNA in the cell cytoplasm. PP1α/γ dephosphorylates MDA5 to allow subsequent signaling. TRIM25 and RIPLET are E3 ubiquitin ligases that ubiquitinate RIG-I for its full activation. The 14-3-3ɛ protein mediates RIG-I translocation to the membrane to interact with MAVS. MAVS is the adaptor protein for both RIG-I and MDA5 and recruits downstream signaling molecules to mediate signaling to the transcription factors IRF3/7 and NFκB. Several aspects of this signaling pathway are inhibited by viruses, as shown here. Abbreviations: coxsackievirus B3 (CVB3), dengue virus (DenV), enterovirus 68 (EV-D68), enterovirus 71 (EV-D71), hepatitis C virus (HCV), human immunodeficiency virus (HIV), molluscum contagiosum virus (MCV), poliovirus (PV), porcine reproductive and respiratory syndrome virus (PRRSV), and West Nile virus (WNV).

Figure 2

Evasion of DNA sensors by viruses. Viral DNA is sensed by cGAS in the cytoplasm and IFI16 in the nucleus. cGAS and IFI16 signal to a common adaptor protein, STING, which recruits TBK1 to activate IRF3, which induces expression of type I IFN and other antiviral genes. IFI16, cGAS, and STING have all been inhibited by viruses, as shown here. Abbreviations: adenovirus (AdV), herpes simplex virus-1 (HSV-1), human immunodeficiency virus (HIV), human papillomavirus 18 (HPV18), and Kaposi's sarcoma associated herpes virus (KSHV).

Figure 3

Viral evasion of the IFN response pathway. Once induced, IFNs are secreted from the infected cell and signal in an autocrine and paracrine manner through the IFN receptor complex to activate the JAK/STAT pathway. This signaling leads to the activation of the ISGF3 complex, which consists of STAT1, STAT2, and IRF9, that translocates to the nucleus to induce ISGs with broad antiviral functions. Both STAT1 and STAT2 are inhibited by viruses, as shown here. Abbreviations: dengue virus (DenV), hepatitis C virus (HCV), and interferon α receptor complex (IFNAR).

Figure 4

Evasion of ISGs by viruses. Both PKR and IFIT1 are ISGs that limit mRNA translation in virally infected cells. PKR phosphorylates the eukaryotic initiation factor eIF2α to inhibit translation. Several viruses, including human cytomegalovirus (HCMV) shown here, inhibit this function of PKR. As IFIT1 binds to uncapped RNAs to prevent their translation, several viruses encode 2′-O methyltransferases that cap viral RNAs to prevent inhibition of their translation during infection. Abbreviations: murine hepatitis virus (MHV), severe acute respiratory syndrome coronavirus (SARS-CoV), vaccinia virus (VACV), and West Nile virus (WNV).