Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Abstract

Infection with Epstein-Barr virus (EBV) affects most humans worldwide and persists life-long in the presence of robust virus-specific T-cell responses. In both immunocompromised and some immunocompetent people, EBV causes several cancers and lymphoproliferative diseases. EBV transforms B cells in vitro and encodes at least 44 microRNAs (miRNAs), most of which are expressed in EBV-transformed B cells, but their functions are largely unknown. Recently, we showed that EBV miRNAs inhibit CD4 + T-cell responses to infected B cells by targeting IL-12, MHC class II, and lysosomal proteases. Here we investigated whether EBV miRNAs also counteract surveillance by CD8 + T cells. We have found that EBV miRNAs strongly inhibit recognition and killing of infected B cells by EBV-specific CD8 + T cells through multiple mechanisms. EBV miRNAs directly target the peptide transporter subunit TAP2 and reduce levels of the TAP1 subunit, MHC class I molecules, and EBNA1, a protein expressed in most forms of EBV latency and a target of EBV-specific CD8 + T cells. Moreover, miRNAmediated down-regulation of the cytokine IL-12 decreases the recognition of infected cells by EBV-specific CD8 + T cells. Thus, EBV miRNAs use multiple, distinct pathways, allowing the virus to evade surveillance not only by CD4 + but also by antiviral CD8 + T cells.adaptive immunity | immune evasion | herpesvirus | CD8 T cells | microRNA E pstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects the majority of the human population worldwide. Although EBV infection persists for life, most carriers remain asymptomatic due to a stringent control by virus-specific immunity. An important component of this immunity is EBV-specific CD8 + T cells, which often expand to high numbers in healthy carriers or after primary infection. Conversely, the absence of EBV-specific CD8 + T cells predicts the emergence of EBVassociated disease in patients after stem cell transplantation or when afflicted with AIDS (1-3). Dangerous EBV-mediated complications can be reversed or prevented by transfer of EBVspecific T cells (4, 5), which further confirms the important role of continuous T-cell control of EBV infection. Among EBVspecific T cells, CD8 + T cells predominate; about 0.05-1% of all CD8 + T cells in healthy donors are typically specific for EBV latent antigens and about twice as many for lytic antigens (6, 7).EBV predominantly infects B cells and establishes a latent infection before production of progeny virus becomes possible (8). Four distinct programs of EBV latent infection have been defined according to their expression profiles of latent viral genes (9-11). One of these programs, known as latency III or the "growth program," is characterized by the expression of a restricted set of approximately eight viral proteins, which activate B cells and drive their proliferation, thus increasing the viral reservoir. Latency III is found in EBV-associated malignancies in immunosuppressed patients (9) and likely reemerges continuously in healthy carriers (9, 12), indicati...

An update: Epstein-Barr virus and immune evasion via microRNA regulation

“…Using EBV mutants that lacked the miRNA clusters, they demonstrated that the EBV miRNAs inhibit antiviral CD4 + T cell responses by targeting IL-12 and peptide processing . At the same time, EBV miRNAs reduce immune surveillance by virus-specific CD8 + T cells (Albanese et al, 2016). The findings are helpful to explain the abundance of miRNAs in the complex virus, and to clarify how EBV can escape elimination for the lifetime of its host in spite of intense adaptive host immune responses.…”

“…Both miR-BHRF1-3 and miR-BART17 target transporter associated with antigen processing 2 (TAP2), which is a mediator of antigenic peptide transportation and EBV epitope presentation (Albanese et al, 2016). EBV miR-BHRF1-2 has a role in the inhibition of PR domaincontaining protein 1 (PRDM1) in lymphoblastoid cell lines .…”

“…In virus infections and tumor proliferation, MICB expression increases, and it has been found to activate NK and T cells, thereby initiating the immune reaction (Diefenbach et al, 2000;Nachmani et al, 2009;Lisnic et al, 2010;Liu et al, 2012). EBV miR-BART1, miR-BART2, and miR-BART22 co-target interleukin-12 (IL-12), leading to decreased T cell differentiation, activation, and recognition at different stages of infection and malignant disease (Albanese et al, 2016). EBV miR-BART3-3p weakens the cytotoxic effect by inhibiting the expression of importin 7 (IPO7), which regulates T cells activation and immune tolerance (Dolken et al, 2010).…”

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

“…Interestingly, KSHV miR-K12-11 mimics this human miRNA (15), and EBV also induces miR-155, because the latent membrane protein 1 (LMP1) of EBV activates its expression (23). Conversely, LMP1 itself is a direct target of several EBV miRNAs (24,25), suggesting that they reduce or limit LMP1 signaling and may thus fine-tune innate immune responses directed against EBV.…”

RNA accessibility impacts potency of Tough Decoy microRNA inhibitors

“…EBV was the first identified virus to produce miRNAs in infected human cells [5]. EBV miRNAs regulate multiple processes in infected cells, such as apoptosis [31–34], EBV-driven cellular transformation [35,36], and immune responses against pathogens [37–42]. As guidelines for the design of the non-complementary TuD sequences are largely lacking, we aimed to determine rules for selecting these nucleotides based on the thermodynamic properties of the TuD structure.…”