EBV and human microRNAs co-target oncogenic and apoptotic viral and human genes during latency

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...

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“…4D). In contrast, LMP1, a known target of EBV miRNAs (43,44), was down-regulated as expected (Fig. 4D).…”

Section: Ebv Mirnas Inhibit Mhc Class I Antigen Processing and Presenmentioning

confidence: 77%

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

Albanese

Tagawa

Bouvet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

133

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“…The let-7a expression and IL-6 production is significantly decreased by the depletion of E2F2 or NF-κB in immune-stimulated cells (Cho et al, 2015). MiR-222, miR-223, the miR-17~92 cluster, and miR-155 are associated with the differentiation of T cells (Riley et al, 2012;Poole and Sinclair, 2015;Saki et al, 2015). EBV-encoded EBNA2 induces the expression of miR-21, consequently promoting B cell transformation and driving the antiviral immune response (Rosato et al, 2012;Zhu et al, 2013).…”

Section: Ebv Latent Proteins Dysregulate Host Mirnas To Regulate the mentioning

confidence: 99%

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

Zuo

Yue

et al. 2017

Virol. Sin.

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Epstein-Barr virus (EBV) is an oncogenic virus that ubiquitously establishes life-long persistence in humans.To ensure its survival and maintain its B cell transformation function, EBV has developed powerful strategies to evade host immune responses. Emerging evidence has shown that microRNAs (miRNAs) are powerful regulators of the maintenance of cellular homeostasis. In this review, we summarize current progress on how EBV utilizes miRNAs for immune evasion. EBV encodes miRNAs targeting both viral and host genes involved in the immune response. The miRNAs are found in two gene clusters, and recent studies have demonstrated that lack of these clusters increases the CD4 + and CD8 + T cell response of infected cells. These reports strongly indicate that EBV miRNAs are critical for immune evasion. In addition, EBV is able to dysregulate the expression of a variety of host miRNAs, which influence multiple immune-related molecules and signaling pathways. The transport via exosomes of EBV-regulated miRNAs and viral proteins contributes to the construction and modification of the inflammatory tumor microenvironment. During EBV immune evasion, viral proteins, immune cells, chemokines, pro-inflammatory cytokines, and pro-apoptosis molecules are involved. Our increasing knowledge of the role of miRNAs in immune evasion will improve the understanding of EBV persistence and help to develop new treatments for EBV-associated cancers and other diseases.

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“…The roles of these BHRF1 miRNAs were unclear until recent in vitro studies using viral knockouts in lymphoblastoid cell lines (LCLs), a widely used cellular model of latency III EBV infection, revealed that the BHRF1 miRNAs cooperate to enhance B cell expansion, reduce levels of latent gene expression, and possibly also inhibit apoptosis (10-12). Additionally, as circumstantial evidence for the roles of these miRNAs, studies that comprehensively examined the targets of EBV miRNAs have shown that BHRF1 miRNAs bind a number of targets involved in proliferation, latent gene expression, and regulation of apoptosis (13,14).…”

Section: Over 90% Of the Adult Human Population Is Chronically Infectmentioning

confidence: 99%

A Cluster of Virus-Encoded MicroRNAs Accelerates Acute Systemic Epstein-Barr Virus Infection but Does Not Significantly Enhance Virus-Induced Oncogenesis In Vivo

Wahl

Linnstaedt

Esoda

et al. 2013

J Virol

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Over 90% of the adult human population is chronically infected with the Epstein-Barr virus (EBV), an oncogenic herpesvirus. EBV primarily infects naive human B cells and persists latently in memory B cells. Most individuals experience an asymptomaticinfection that is effectively controlled by the adaptive immune response. However, EBV-associated lymphomas can develop in immunocompromised individuals. These tumors typically express all nine EBV latent proteins (latency III). Latency III is also associated with the expression of three precursor microRNAs (miRNAs) located within the EBV BHRF1 gene locus. The role of these BHRF1 miRNAs was unclear until recent in vitro studies demonstrated that they cooperate to enhance virus-induced B cell transformation and decrease the antigenic load of virus-infected cells, indicating that the BHRF1 miRNA cluster may serve as a novel therapeutic target for the treatment of latency III EBV-associated malignancies. However, to date, it is not known if BHRF1 miRNAs enhance virus-induced oncogenesis and/or immune evasion of EBV in vivo. To understand the in vivo contribution of the BHRF1 miRNA cluster to EBV infection and EBV-associated tumorigenesis, we monitored EBV infection and assessed tumor formation in humanized mice exposed to wild-type virus and a viral mutant (⌬123) that lacks all three BHRF1 miRNAs. Our results demonstrate that while the BHRF1 miRNAs facilitate the development of acute systemic EBV infection, they do not enhance the overall oncogenic potential of EBV in vivo.E pstein-Barr Virus (EBV), a human gamma herpesvirus, is widespread in all populations; more than 90% of adults worldwide have antibodies to EBV, and infection with EBV persists for the life of its host (1). In healthy individuals, EBV is effectively controlled by the immune system and typically remains asymptomatic. Upon primary infection, virus-targeted B cells undergo a period of rapid proliferation until either CD8 ϩ T cells mount an efficient antiviral response (2) or infected B cells differentiate into a pool of latently infected memory-like B cells (3). When the immune system is suppressed, EBV can induce the development of certain lymphomas (4-6).EBV-associated malignancies that arise in immunodeficient individuals (i.e., posttransplant and AIDS patients) typically express all nine EBV latent proteins (latency III): six Epstein-Barr virus nuclear antigens (EBNA) and three latent membrane proteins (LMP) (1, 3). Although most EBV-associated malignancies respond poorly to chemotherapy, immunotherapy approaches that boost or supplement the patient's EBV-specific T cell response have been successful in treating some latency III tumors due to their high antigenic load (4). However, these strategies, which typically involve the adoptive transfer of autologous or allogeneic EBV-specific T cells stimulated in vitro, are often laborious and technically challenging (4). Therefore, new therapeutic targets and approaches are urgently needed for the treatment of EBV-associated malignancies.In addition to th...

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EBV and human microRNAs co-target oncogenic and apoptotic viral and human genes during latency

Cited by 254 publications

References 109 publications

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

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

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

A Cluster of Virus-Encoded MicroRNAs Accelerates Acute Systemic Epstein-Barr Virus Infection but Does Not Significantly Enhance Virus-Induced Oncogenesis In Vivo

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EBV and human microRNAs co-target oncogenic and apoptotic viral and human genes during latency

Cited by 254 publications

References 109 publications

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

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

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

A Cluster of Virus-Encoded MicroRNAs Accelerates Acute Systemic Epstein-Barr Virus Infection but Does Not Significantly Enhance Virus-Induced Oncogenesis In Vivo

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

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