K1 and K15 of Kaposi's Sarcoma-Associated Herpesvirus Are Partial Functional Homologues of Latent Membrane Protein 2A of Epstein-Barr Virus

Steinbrück, Lisa; Gustems, Montse; Medele, Stephanie; Schulz, Thomas F.; Lutter, Dominik; Hammerschmidt, Wolfgang

doi:10.1128/jvi.00839-15

Cited by 45 publications

(74 citation statements)

References 62 publications

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“…We started this study by refining our previous data (Steinbrück et al, 2015) to determine the parameters of infection and to identify the optimal ratio of EBV versus human primary Blymphocytes. We infected them with different multiplicities of infection (MOIs) of wt/ B95.8 (2089) EBV (Tab.…”

Section: Latent Phase Of Ebv Infectionmentioning

confidence: 99%

The first days in the life of naïve human B-lymphocytes infected with Epstein-Barr virus

Pich

Mrozek-Górska

Bouvet

et al. 2019

Preprint

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Epstein-Barr virus (EBV) infects and activates resting human B-lymphocytes, reprograms them, induces their proliferation, and establishes a latent infection in them. In established EBV-infected cell lines many viral latent genes are expressed. Their roles in supporting the continuous proliferation of EBV-infected B cells in vitro are known, but their functions in the early, pre-latent phase of infection have not been investigated systematically. In studies during the first eight days of infection using derivatives of EBV with mutations in single genes of EBVs we found only EBNA2 to be essential for activating naïve human B-lymphocytes, inducing their growth in cell volume, driving them into rapid cell divisions, and preventing cell death in a subset of infected cells. EBNA-LP, LMP2A and the viral microRNAs have supportive, auxiliary functions, but mutants of LMP1, EBNA3A, EBNA3C, and the noncoding EBER RNAs had no discernable phenotype compared with wild-type EBV. B cells infected with a double mutant of EBNA3A and 3C had an unexpected proliferative advantage and did not regulate the DNA damage response (DDR) of the infected host cell in the pre-latent phase. Even EBNA1 which has very critical longterm functions in maintaining and replicating the viral genomic DNA in established cell lines, was dispensable for the early activation of infected cells. Our findings document that the virus dose is a critical parameter and indicate that EBNA2 governs the infected cells initially and implements a strictly controlled temporal program independent of other viral latent genes. It thus appears that EBNA2 is sufficient to control all requirements for clonal cellular expansion and to reprogram human B-lymphocytes from energetically quiescent to activated cells. Author summaryThe preferred target of Epstein-Barr virus (EBV) are human resting B-lymphocytes. We found that their infection induces a well-coordinated, time-driven program that starts with a substantial 3 increase in cell volume followed by cellular DNA synthesis after three days and subsequent rapid rounds of cell divisions on the next day accompanied by some DNA replication stress (DRS). Two to three days later the cells decelerate and turn into stably proliferating lymphoblast cell lines. With the aid of 16 different recombinant EBV strains we investigated the individual contributions of EBV's multiple latent genes during early B-cell infection and found that many do not exert a detectable phenotype or contribute little to EBV's pre-latent phase. The exception is EBNA2 that is essential in governing all aspects of B-cell reprogramming. EBV relies on EBNA2 to turn the infected B-lymphocytes into proliferating lymphoblasts preparing the infected host cell for the ensuing stable, latent phase of viral infection. In the early steps of B-cell reprogramming viral latent genes other than EBNA2 are dispensable but some, EBNA-LP for example, support the viral program and presumably stabilize the infected cells once viral latency is established.

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Section: Latent Phase Of Ebv Infectionmentioning

confidence: 99%

The first days in the life of naïve human B-lymphocytes infected with Epstein-Barr virus

Pich

Mrozek-Górska

Bouvet

et al. 2019

Preprint

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“…KSHV also encodes two other transmembrane proteins K1, which mimics the B-cell receptor (BCR), and K15 (Steinbruck et al, 2015). K1 and K15 are partial functional homologues to the latent membrane protein 2A (LMP2A) encoded by a related gammaherpesvirus, Epstein-Barr virus (EBV).…”

Section: Viral Transmembrane Proteins: Kshv Vgpcr K1 and K15 And Tmentioning

confidence: 99%

Modulation of oncogenic signaling networks by Kaposi’s sarcoma-associated herpesvirus

Wong

Damania

2017

Biological Chemistry

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of three human malignancies Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. To persist and replicate within host cells, KSHV encodes proteins that modulate different signaling pathways. Manipulation of cell survival and proliferative networks by KSHV can promote the development of KSHV-associated malignancies. In this review, we discuss recent updates on KSHV pathogenesis and the viral life cycle. We focus on proteins encoded by KSHV that modulate the phosphatidylinositol-4,5-bisphosphate 3 kinase and extracellular signal-regulated kinases 1/2 pathways to create an environment favorable for viral replication and the development of KSHV malignancies.

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“…Stocks of recombinant EBV strains were essentially prepared and quantitated as described (65). Details can be found in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

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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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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K1 and K15 of Kaposi's Sarcoma-Associated Herpesvirus Are Partial Functional Homologues of Latent Membrane Protein 2A of Epstein-Barr Virus

Cited by 45 publications

References 62 publications

The first days in the life of naïve human B-lymphocytes infected with Epstein-Barr virus

The first days in the life of naïve human B-lymphocytes infected with Epstein-Barr virus

Modulation of oncogenic signaling networks by Kaposi’s sarcoma-associated herpesvirus

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

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K1 and K15 of Kaposi's Sarcoma-Associated Herpesvirus Are Partial Functional Homologues of Latent Membrane Protein 2A of Epstein-Barr Virus

Cited by 45 publications

References 62 publications

The first days in the life of naïve human B-lymphocytes infected with Epstein-Barr virus

The first days in the life of naïve human B-lymphocytes infected with Epstein-Barr virus

Modulation of oncogenic signaling networks by Kaposi’s sarcoma-associated herpesvirus

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

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Product

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