Souza TA, Stollar BD, Sullivan JL, et al. Peripheral B cells latently infected with Epstein-Barr virus display molecular hallmarks of classical antigen-selected memory B cells. Proc Natl Acad Sci U S A. 2005;102:18093-8

Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2006; 102(50):18093-8. DOI: 10.1073/pnas.0509311102
Source: PubMed


Epstein-Barr virus (EBV) establishes a lifelong persistent infection within peripheral blood B cells with the surface phenotype of memory cells. To date there is no proof that these cells have the genotype of true germinal-center-derived memory B cells. It is critical to understand the relative contribution of viral mimicry versus antigen signaling to the production of these cells because EBV encodes proteins that can affect the surface phenotype of infected cells and provide both T cell help and B cell receptor signals in the absence of cognate antigen. To address these questions we have developed a technique to identify single EBV-infected cells in the peripheral blood and examine their expressed Ig genes. The genes were all isotype-switched and somatically mutated. Furthermore, the mutations do not cause stop codons and display the pattern expected for antigen-selected memory cells based on their frequency, type, and location within the Ig gene. We conclude that latently infected peripheral blood B cells display the molecular hallmarks of classical antigen-selected memory B cells. Therefore, EBV does not disrupt the normal processing of latently infected cells into memory, and deviations from normal B cell biology are not tolerated in the infected cells. This article provides definitive evidence that EBV in the peripheral blood persists in true memory B cells.

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Available from: John L. Sullivan, Aug 24, 2015
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    • "The standard model for many years has been in vitro B cell transformation by Epstein-Barr virus (EBV) (1), which is independent of normal lymphoid tissue organization. However, in vivo EBV persists not in proliferating blasts but in resting memory B cells (2, 3) that show evidence of passage through germinal centers (GCs) (4). Thus, there is discrepancy between in vitro and in vivo virus behaviors. "
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    ABSTRACT: Lymphocyte colonization by gammaherpesviruses (γHVs) is an important target for cancer prevention. However, how it works is not clear. Epstein-Barr virus drives autonomous B cell proliferation in vitro but in vivo may more subtly exploit the proliferative pathways provided by lymphoid germinal centers (GCs). Murid herpesvirus 4 (MuHV-4), which realistically infects inbred mice, provides a useful tool with which to understand further how a γHV colonizes B cells in vivo. Not all γHVs necessarily behave the same, but common events can with MuHV-4 be assigned an importance for host colonization and so a potential as therapeutic targets. MuHV-4-driven B cell proliferation depends quantitatively on CD4+ T cell help. Here we show that it also depends on T cell-independent survival signals provided by the B cell-activating factor (BAFF) receptor (BAFF-R). B cells could be infected in BAFF-R−/− mice, but virus loads remained low. This corresponded to a BAFF-R-dependent defect in GC colonization. The close parallels between normal, antigen-driven B cell responses and virus-infected B cell proliferation argue that in vivo, γHVs mostly induce infected B cells into normal GC reactions rather than generating large numbers of autonomously proliferating blasts. IMPORTANCE γHVs cause cancers by driving the proliferation of infected cells. B cells are a particular target. Thus, we need to know how virus-driven B cell proliferation works. Controversy exists as to whether viral genes drive it directly or less directly orchestrate the engagement of normal, host-driven pathways. Here we show that the B cell proliferation driven by a murid γHV requires BAFF-R. This supports the idea that γHVs exploit host proliferation pathways and suggests that interfering with BAFF-R could more generally reduce γHV-associated B cell proliferation.
    Journal of Virology 02/2014; 88(8). DOI:10.1128/JVI.03497-13 · 4.44 Impact Factor
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    • "EBV establishes a lifelong persistent infection within peripheral blood B cells with no or extremely low LMP1 expression [3], [4]. LMP1 acts as a constitutively active, receptor-like molecule [5] and activates a variety of cellular genes that enhance cell survival, adhesive, invasive, and angiogenic potential. "
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    ABSTRACT: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus. Toll-like receptor 7 (TLR7) is involved in host innate immunity against pathogens, and its aberrant activation is linked to the development of systemic lupus erythematosus (SLE, also called "lupus"). Type I interferons (IFN) are apparently driving forces for lupus pathogenesis. Previously, we found that EBV latent membrane protein 1 (LMP1) primes cells for IFN production. In this report, the relationship among EBV LMP1, TLRs, and IFN production are examined. We find that TLR7 activation increases the expression of EBV LMP1, and IFN regulatory factor 7 (IRF7) is involved in the stimulation process. TLR7 activation did not induce IFNs from EBV-infected cells, but potentiates those cells for IFN production by TLR3 or TLR9 activation. In addition, we find that LMP1 and IFNs are co-expressed in the same cells in some lupus patients. Therefore, the aberrant activation of TLR7 might induce LMP1 expression and LMP1-expression cells may be producing IFNs in lupus patients. These results suggest EBV might be an exacerbating factor in some lupus patients via promoting IFN production.
    PLoS ONE 08/2012; 7(8):e43317. DOI:10.1371/journal.pone.0043317 · 3.23 Impact Factor
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    • "The switch from proliferation to in vivo latency in memory B cells is still poorly understood. The presence of EBV does not appear to interfere with the physiological germinal centre reaction, including somatic hypermutation, class switch recombination and development of memory B cells (Souza et al, 2005). No viral gene product appears to be required to maintain the virus in its latent state in latently infected resting memory B cells in vivo (except for EBNA1 during rare cell divisions as part of the homeostatic regulation of the B cell pool) and likewise, no viral gene product appears to be expressed (except EBNA1 in these rare mitoses). "
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    ABSTRACT: The particular epidemiological features of Burkitt lymphoma (BL) in Tropical Africa, first described by Denis Burkitt in 1958, initiated the search for a virus that induces malignant B cell lymphomas in humans and is transmitted by arthropods. The herpes virus (Epstein‐Barr virus, EBV) discovered by Epstein and collaborators in cell lines established from BL biopsies fulfilled some of these predictions. It drives primary B cells into unlimited proliferation, induces malignant B cell lymphomas in immunocompromised individuals (post‐transplant lympho‐proliferative disease, PTLD) in vivo, and footprints of the virus are generally detected in African BL biopsies supporting a causative role of the virus in the pathogenesis of BL. The virus is, however, not transmitted by arthropods and is spread ubiquitously amongst the human population through saliva. Furthermore, BL and EBV‐induced PTLD are now recognized as pathogenetically distinct entities: BL involves MYC‐immunoglobulin translocations in contrast to PTLD, and different patterns of viral genes are expressed in both diseases. Viral gene products expressed in BL are assumed to contribute to inhibition of apoptosis, although their precise mechanism of action is not fully understood. In the future, next generation sequencing is expected to shed more light on the contribution of EBV to the pathogenesis of BL.
    British Journal of Haematology 03/2012; 156(6):719-29. DOI:10.1111/j.1365-2141.2011.09007.x · 4.71 Impact Factor
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