Cells Expressing the Epstein-Barr Virus Growth Program Are Present in and Restricted to the Naive B-Cell Subset of Healthy Tonsils

Joseph, Alexandra; Babcock, Gregory J.; Thorley‐Lawson, David A.

doi:10.1128/jvi.74.21.9964-9971.2000

Cited by 100 publications

(95 citation statements)

References 42 publications

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“…We propose that viral reactivation results in de novo infection of a subset of IgD ϩ naive B cells, providing a mechanism for maintaining the longterm viral reservoir in wild-type mice. This possibility is supported by the observation that EBV infection of naive tonsillar B cells correlated with active viral replication in the tonsils (63). We hypothesize that memory B cell triggering fails to occur in SAPdeficient mice because of SAP-associated defects in B cell activation, resulting in the absence of virally infected naive B cells.…”

Section: Discussionmentioning

confidence: 76%

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

Kim

Burkum

Cookenham

et al. 2007

The Journal of Immunology

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Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP)) interactions with SLAM family proteins play important roles in immune function. SAP-deficient mice have defective B cell function, including impairment of germinal center formation, production of class-switched Ig, and development of memory B cells. B cells are the major reservoir of latency for both EBV and the homologous murine gammaherpesvirus, gammaherpesvirus 68. There is a strong association between the B cell life cycle and viral latency in that the virus preferentially establishes latency in activated germinal center B cells, which provides access to memory B cells, a major reservoir of long-term latency. In the current studies, we have analyzed the establishment and maintenance of γHV68 latency in wild-type and SAP-deficient mice. The results show that, despite SAP-associated defects in germinal center and memory B cell formation, latency was established and maintained in memory B cells at comparable frequencies to wild-type mice, although the paucity of memory B cells translated into a 10-fold reduction in latent load. Furthermore, there were defects in normal latency reservoirs within the germinal center cells and IgD+“naive” B cells in SAP-deficient mice, showing a profound effect of the SAP mutation on latency reservoirs.

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Section: Discussionmentioning

confidence: 76%

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

Kim

Burkum

Cookenham

et al. 2007

The Journal of Immunology

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“…RT-PCR was used to determine the expression of EBV genes indicative of viral replication and the three latency programs. The details of this assay have been published previously (7). Serial dilutions of isolated cell populations were prepared and aliquoted into Eppendorf tubes.…”

Section: Rt-pcrmentioning

confidence: 99%

“…This is evident from our previous studies in which we have shown that defined patterns of EBV gene expression are associated with specific populations of mature B cells. In the tonsils of healthy individuals, naive B cells, which are thought to be newly infected, express all nine known latency proteins (Epstein-Barr nuclear Ag 1 (EBNA1), 4 EBNA2, EBNA3a, EBNA3b, EBNA3c, and LP and latent membrane protein (LMP)1, LMP2a, and LMP2b) (7,8); infected germinal center and memory B cells express a limited set of three latency proteins (LMP1, LMP2a, and EBNA1(Q-K)) (8,9); and infected memory B cells in the blood cease expression of all viral proteins, with the exception that they express EBNA1 when they divide (4). Viral replication occurs in tonsillar plasma cells, resulting in expression of the lytic genes including BZLF1 (10).…”

mentioning

confidence: 99%

EBV and Systemic Lupus Erythematosus: A New Perspective

Gross

Hochberg²,

Rand

et al. 2005

The Journal of Immunology

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201

178

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We have proposed that EBV uses mature B cell biology to access memory B cells as a site of persistent infection. A central feature of this model is that EBV adapts its gene expression profile to the state of the B cell it resides in and that the level of infection is stable over time. This led us to question whether changes in the behavior or regulation of mature B cells would alter the state of EBV persistence. To investigate this, we studied the impact of systemic lupus erythematosus (SLE), a disease characterized by immune dysfunction, on EBV infection. We show that patients with SLE have abnormally high frequencies of EBV-infected cells in their blood, and this is associated with the occurrence of SLE disease flares. Although patients with SLE have frequencies of infected cells comparable to those seen in immunosuppressed patients, in SLE the effect was independent of immunosuppressive therapy. Aberrant expression of viral lytic (BZLF1) and latency (latency membrane proteins 1 and 2a) genes was also detected in the blood of SLE patients. We conclude that the abnormal regulation of EBV infection in SLE patients reflects the sensitivity of the virus to perturbation of the immune system.

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“…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), indicating that its control is critical for the health of an EBV carrier. Only at a later stage of infection (13) can the virus enter its lytic phase in infected cells to produce progeny virions, a phase requiring expression of the majority of viral proteins.…”

mentioning

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.

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...

show abstract

Cells Expressing the Epstein-Barr Virus Growth Program Are Present in and Restricted to the Naive B-Cell Subset of Healthy Tonsils

Abstract: In this paper we demonstrate, for the first time, that Epstein-Barr virus (EBV)-

Cited by 100 publications

References 42 publications

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

EBV and Systemic Lupus Erythematosus: A New Perspective

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

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Cells Expressing the Epstein-Barr Virus Growth Program Are Present in and Restricted to the Naive B-Cell Subset of Healthy Tonsils

Abstract: In this paper we demonstrate, for the first time, that Epstein-Barr virus (EBV)-

Cited by 100 publications

References 42 publications

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

EBV and Systemic Lupus Erythematosus: A New Perspective

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