Co-Infection of the Epstein–Barr Virus and the Kaposi Sarcoma-Associated Herpesvirus

Böni, Michelle; Rieble, Lisa; Münz, Christian

doi:10.3390/v14122709

Cited by 13 publications

(5 citation statements)

References 216 publications

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“…In support, multiple family members encode BALF0/1 homologs (75). However, since KSHV frequently superinfects EBV+ cells (76), it is plausible that KSHV relies upon EBV BALF0/1 to downregulate BCR, perhaps enabling the KSHV-encoded homolog to have evolved distinct functions.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr Virus BALF0/1 Subverts the Caveolin and ERAD Pathways to Target B-cell Receptor Complexes for Degradation

Yiu,

Weekes,

Gewurz

2024

Preprint

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Epstein–Barr virus (EBV) establishes persistent infection, causes infectious mononucleosis, is a major trigger for multiple sclerosis and contributes to multiple cancers. Yet, knowledge remains incomplete about how the virus remodels host B cells to support lytic replication. We previously identified that EBV lytic replication results in selective depletion of plasma membrane B-cell receptor (BCR) complexes, comprised of immunoglobulin and the CD79A and CD79B signaling chains. Here, we used proteomic and biochemical approaches to identify that the EBV early lytic protein BALF0/1 is responsible for EBV lytic cycle BCR degradation. Mechanistically, an immunoglobulin heavy chain cytoplasmic tail KVK motif was required for ubiquitin-mediated BCR degradation, while CD79A and CD79B were dispensable. BALF0/1 subverted caveolin-mediated endocytosis to internalize plasma membrane BCR complexes and to deliver them to the endoplasmic reticulum. BALF0/1 stimulated immunoglobulin heavy chain cytoplasmic tail ubiquitination, which together with the ATPase valosin-containing protein/p97 drove ER-associated degradation of BCR complexes by cytoplasmic proteasomes. BALF0/1 knockout reduced the viral load of secreted EBV particles from B-cells that expressed a monoclonal antibody against EBV glycoprotein 350 and increased viral particle immunoglobulin incorporation. Consistent with downmodulation of plasma membrane BCR, BALF0/1 overexpression reduced viability of a diffuse large B-cell lymphoma cell line dependent upon BCR signaling. Collectively, our results suggest that EBV BALF0/1 downmodulates immunoglobulin upon lytic reactivation to block BCR signaling and support virion release.SIGNIFICANCEEBV uses a biphasic lifecycle, in which it switches between a latent state that facilitates immune evasion and a lytic state, where virion are secreted. However, when EBV infects a B-cell that makes antibody against a virion protein, EBV must have a strategy to escape becoming trapped, since maturing virion and antibody each traffic through the secretory pathway. We identified that an EBV-encoded protein expressed, BALF0/1, associates with and targets immunoglobulin complexes for degradation. Intriguingly, BALF0/1 subverts the caveolin-1 and ERAD pathways to route antibody from the plasma membrane to cytoplasmic proteasomes for degradation. We present evidence that this enhances EBV secretion from cells that produce antibody against a viral glycoprotein, which could otherwise trap virus.

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Section: Discussionmentioning

confidence: 99%

Epstein–Barr Virus BALF0/1 Subverts the Caveolin and ERAD Pathways to Target B-cell Receptor Complexes for Degradation

Yiu,

Weekes,

Gewurz

2024

Preprint

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“…Therefore, many studies have targeted relationships among the microenvironment, oncogenesis, tumor growth, and dissemination. How EBV and KSHV support each other in terms of persistence and lymphangiogenesis has been explained in recent reviews ( 268 ), ( 269 ). A relationship between EBV and HCV replication markers has not been identified in patients with AIDS ( 270 ), which is in contrast to other known coinfections.…”

Section: Discussionmentioning

confidence: 99%

Carcinogenic mechanisms of virus-associated lymphoma

Zhang,

Guo,

Zhan

et al. 2024

Front. Immunol.

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The development of lymphoma is a complex multistep process that integrates numerous experimental findings and clinical data that have not yet yielded a definitive explanation. Studies of oncogenic viruses can help to deepen insight into the pathogenesis of lymphoma, and identifying associations between lymphoma and viruses that are established and unidentified should lead to cellular and pharmacologically targeted antiviral strategies for treating malignant lymphoma. This review focuses on the pathogenesis of lymphomas associated with hepatitis B and C, Epstein-Barr, and human immunodeficiency viruses as well as Kaposi sarcoma-associated herpesvirus to clarify the current status of basic information and recent advances in the development of virus-associated lymphomas.

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“…EBV has been shown to inhibit chemically induced lytic replication of KSHV [ 45 ]. In primary effusion lymphoma (PEL), KSHV is necessary but often involves co-infection with EBV, and these two viruses have been shown to interact to alter cell proliferation [ 46 ] suggesting KSHV and EBV interactions that are important to disease development. However, the mechanisms behind these interactions are relatively undefined and require further study.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus (EBV) antibody changes over time in a general population cohort in rural Uganda, 1992–2008

Sabourin,

Mugisha,

Asiki

et al. 2023

Infect Agents Cancer

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Background Epstein–Barr virus (EBV) infection is ubiquitous and in sub-Saharan Africa, occurs early in life. In a population-based rural African cohort, we leveraged historical samples from the General Population Cohort (GPC) in Uganda to examine the epidemiology of infection with EBV over time, in the era of HIV. Methods We used 9024 serum samples collected from the GPC in 1992, 2000, 2008, from 7576 participants across the age range (0–99 years of age) and tested for anti-EBV immunoglobulin G (IgG) antibodies to EAd, VCA, and EBNA-1 using a multiplex bead-based assay. The related gammaherpesvirus, Kaposi’s sarcoma-associated herpesvirus (KSHV) seropositivity was also determined by detection of anti-KSHV IgG antibodies to K8.1 or ORF73 measured by recombinant protein enzyme-linked immunosorbent assay. Data on sex, age, and HIV serostatus were also collected. EBV seropositivity was modeled with age (excluding those under one year, who may have had maternal antibodies), sex, HIV serostatus, and KSHV serostatus using generalized linear mixed effects models to produce beta estimates. Results More than 93% of children were EBV seropositive by one year of age. EBV seropositivity was significantly associated with KSHV seropositivity. Anti-EBNA-1 antibody levels decreased with increasing age and were lower on average in people living with HIV. In general, anti-EAd antibody levels increased with age, were higher in males and KSHV seropositive persons, but decreased over calendar time. Anti-VCA antibody levels increased with age and with calendar time and were higher in KSHV seropositive persons but lower in males. Conclusions This is the first study to identify factors associated with EBV antibodies across the entire life-course in rural sub-Saharan Africa. Consistent with other studies, EBV was near ubiquitous in the population by age one year. Patterns of antibodies show changes by age, sex and calendar time, but no association with HIV was evident, suggesting no relationship between EBV sero-epidemiology and the spread of HIV in the population over time in Uganda.

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Co-Infection of the Epstein–Barr Virus and the Kaposi Sarcoma-Associated Herpesvirus

Cited by 13 publications

References 216 publications

Epstein–Barr Virus BALF0/1 Subverts the Caveolin and ERAD Pathways to Target B-cell Receptor Complexes for Degradation

Epstein–Barr Virus BALF0/1 Subverts the Caveolin and ERAD Pathways to Target B-cell Receptor Complexes for Degradation

Carcinogenic mechanisms of virus-associated lymphoma

Epstein–Barr virus (EBV) antibody changes over time in a general population cohort in rural Uganda, 1992–2008

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