RNAs in Epstein–Barr virions control early steps of infection

Jochum, Simon; Ruiss, Romana; Moosmann, Andreas; Hammerschmidt, Wolfgang; Zeidler, Reinhard

doi:10.1073/pnas.1115906109

Cited by 76 publications

(102 citation statements)

References 65 publications

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“…The mechanisms of regulation we identified in that context-that is, regulation of MHC II, lysosomal enzymes, and IL-12-are likely relevant in latency as well and may explain why EBNA-specific CD4 + T cells are generally impaired in recognizing LCLs (46). The present study focused on established latency, but because we observed a strong miRNA regulation of EBNA1 recognition by CD8 + T cells already on days 1, 2, and 3 after infection, the hypothesis that EBV miRNAs generally suppress CD8 + T-cell recognition already in the first days of infection during prelatency (13,22,47) deserves closer investigation in the future.…”

Section: Discussionmentioning

confidence: 58%

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.

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137

133

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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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Section: Discussionmentioning

confidence: 58%

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.

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137

133

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“…Indeed, chronic activation of antiviral immunity by erroneous detection of extracellular RNA drives autoimmunity in predisposed individuals (20). Although binding of proinflammatory EBERs to cytoplasmic sensors has been reported in vitro (9)(10)(11)(12), there is little evidence that this may occur in latently infected B cells in a physiologically relevant context (21), but there are multiple indications that EBERs are secreted from infected cells (9,22,23).…”

Section: Significancementioning

confidence: 99%

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Baglio¹,

Eijndhoven²,

Koppers-Lalić

et al. 2016

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

144

145

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Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein-Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viraland exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5′ppp, in vitro transcripts, and coculture experiments, we established that 5′pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non-cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host-pathogen stand-off and may promote inflammatory disease.exosomes | EBV-EBER1 | innate sensing | dendritic cells | skin inflammation

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“…The primary infection of B cells by EBV shows an expression of lytic genes (21)(22)(23). The expression of the lytic genes before the latent genes during early infection suggests that this initial expression of lytic genes is important for the successful establishment of EBV latency (21,22).…”

mentioning

confidence: 99%

Transcriptome Analysis of Kaposi's Sarcoma-Associated Herpesvirus during De Novo Primary Infection of Human B and Endothelial Cells

Purushothaman

Thakker

Verma

2015

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV8), is a double-stranded DNA virus that causes Kaposi's sarcoma, primary effusion lymphomas, and multicentric Castleman's disease (1-3). Like other herpesviruses, KSHV exhibits both latent and lytic modes of infection, persisting predominantly in the latent state in which only a subset of the viral proteins are expressed, including the latency-associated nuclear antigen (LANA) protein (4-8). Although the expression of latent proteins plays a critical role in inducing and maintaining KSHV latency, the infected cells are primed early during the primary infection to retain the viral genomes and induce tumors (9). During the primary infection, KSHV undergoes a short lytic replication cycle that transcribes an array of viral genes, which have been shown to modulate various pathways for establishing the latent infection (9). In addition, a small fraction (1 to 5%) of the infected cells spontaneously undergo lytic reactivation to produce infectious virions, which is likely to be essential for increasing the population of infected cells and inducing viral pathogenesis (10-13).The infection of target cells with KSHV is a complex multistep process involving a variety of host cell surface receptors and multiple viral glycoproteins. Irrespective of its mechanism of entry, for a successful infection, KSHV must overcome the obstacles it encounters during the transportation of viral capsids from the plasma membrane into the nucleus. The main obstacles include

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RNAs in Epstein–Barr virions control early steps of infection

Cited by 76 publications

References 65 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

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Transcriptome Analysis of Kaposi's Sarcoma-Associated Herpesvirus during De Novo Primary Infection of Human B and Endothelial Cells

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RNAs in Epstein–Barr virions control early steps of infection

Cited by 76 publications

References 65 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

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Transcriptome Analysis of Kaposi's Sarcoma-Associated Herpesvirus during De Novo Primary Infection of Human B and Endothelial Cells

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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