MicroRNAs of Epstein-Barr Virus Control Innate and Adaptive Antiviral Immunity

Abstract

Epstein-Barr virus (EBV) has established lifelong infection in more than 90% of humanity. While infection is usually controlled by the immune system, the human host fails to completely eliminate the pathogen. Several herpesviral proteins are known to act as immunoevasins, preventing or reducing recognition of EBV-infected cells. Only recently were microRNAs of EBV identified to reduce immune recognition further. This Gem summarizes what we know about immunomodulatory microRNAs of herpesviruses.

Keywords: cancer; human herpesviruses; immune evasion; immune surveillance; microRNA.

FIG 1

Immunoevasive functions of herpesviral miRNAs. miRNAs of the human herpesviruses EBV, KSHV, and CMV target cellular and viral genes regulating the antiviral responses of innate and adaptive immunity. Shown are key genes downregulated by viral miRNAs. TLR, Toll-like receptor.

FIG 2

EBV miRNAs globally control antiviral adaptive immune responses in infected cells. Upon infection, the viral DNA genome circularizes, and viral coding and noncoding RNAs are expressed immediately. EBV miRNAs support the evasion of adaptive immunity at several levels. 1, Viral miRNAs downregulate viral transcripts to limit viral antigen synthesis: miR-BART22 controls LMP2A/B, several BART miRNAs control LMP1, and EBNA1 is controlled by unidentified viral miRNAs; 2, reduced levels of LMP1 may lead to lower levels of antigen presentation because LMP1 activates coreceptors and MHC expression; 3, viral miRNAs control antigen processing for MHC class I-mediated presentation regulating the expression of TAP2, a target of miR-BHRF1-3 and -BART17; 4, miR-BART1 and -BART2 control the expression of the lysosomal enzymes IFI30 and LGMN, respectively; a third lysosomal enzyme, CTSB, is controlled by both miR-BART2 and -BHRF1-2, reducing the capacity to present antigenic epitopes on MHC class II molecules to CD4⁺ T cells; 5, secretion of the NK cell ligand CXCL-11 is reduced by miR-BHRF1-3 while the mRNA encoding inflammatory cytokine IL-12 (and two additional cytokines, IL-12B and IL-23) is directly bound by five EBV miRNAs, resulting in suppressed Th1 differentiation. Other inflammatory cytokines, such as IL-6, are also reduced by viral miRNAs.