scholarly journals Molecular basis of EphA2 recognition by gHgL from gammaherpesviruses

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chao Su ◽  
Lili Wu ◽  
Yan Chai ◽  
Jianxun Qi ◽  
Shuguang Tan ◽  
...  
Keyword(s):  
Kaposi Sarcoma ◽  
Cell Tropism ◽  
Viral Glycoprotein ◽  
Potential Threat ◽  
Binding Characteristics ◽  
Barr Virus ◽  
Glycoprotein H ◽  
Specific Receptors ◽  
Epstein Barr ◽  
Entry Receptor

AbstractThe human γ-herpesviruses Kaposi sarcoma associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are associated with many human malignancies. Viral glycoprotein H (gH) and glycoprotein L (gL) are crucial for the cell tropism by binding to specific receptors. Recently, EphA2 was identified as the specific entry receptor for both KSHV and EBV. Here, we characterized the crystal structures of KSHV gHgL or EBV gHgL in complex with the ligand binding domain (LBD) of EphA2. Both KSHV and EBV gHgL bind to the channel and peripheral regions of LBD primarily using gL. Extensive interactions with more contacts contribute to the higher affinity of KSHV gHgL to LBD than that of EBV gHgL. These binding characteristics were verified using cell-based fusion assays with mutations in key EphA2 residues. Our experiments suggest that multiple animal γ-herpesviruses could use EphA2 as an entry receptor, implying a potential threat to human health.

scholarly journals Determinants of Gammaherpesvirus Shedding in Saliva Among Ugandan Children and Their Mothers

2018 ◽  
Vol 218 (6) ◽  
pp. 892-900 ◽  
Author(s):  
Robert Newton ◽  
Nazzarena Labo ◽  
Katie Wakeham ◽  
Vickie Marshall ◽  
Romin Roshan ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Kaposi Sarcoma ◽  
Parasitic Infections ◽  
Viral Shedding ◽  
Barr Virus ◽  
Epstein Barr

Among Ugandan mother-child pairs, Epstein-Barr virus was more likely to be shed in saliva than Kaposi sarcoma–associated virus. Child’s sex and parasitic infections influenced viral shedding. Shedding of each virus was inversely related, suggesting an interaction between them.

scholarly journals Dangerous Liaisons: Gammaherpesvirus Subversion of the Immunoglobulin Repertoire

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 788
Author(s):  
Monika A. Zelazowska ◽  
Kevin McBride ◽  
Laurie T. Krug
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Adaptive Immune Response ◽  
Kaposi Sarcoma ◽  
Lymphoid Tissues ◽  
Barr Virus ◽  
Sequencing Technologies ◽  
Biologic Property ◽  
Epstein Barr ◽  
Immunoglobulin Repertoire

A common biologic property of the gammaherpesviruses Epstein–Barr Virus and Kaposi sarcoma herpesvirus is their use of B lymphocytes as a reservoir of latency in healthy individuals that can undergo oncogenic transformation later in life. Gammaherpesviruses (GHVs) employ an impressive arsenal of proteins and non-coding RNAs to reprogram lymphocytes for proliferative expansion. Within lymphoid tissues, the germinal center (GC) reaction is a hub of B cell proliferation and death. The goal of a GC is to generate and then select for a pool of immunoglobulin (Ig) genes that will provide a protective humoral adaptive immune response. B cells infected with GHVs are detected in GCs and bear the hallmark signatures of the mutagenic processes of somatic hypermutation and isotype class switching of the Ig genes. However, data also supports extrafollicular B cells as a reservoir engaged by GHVs. Next-generation sequencing technologies provide unprecedented detail of the Ig sequence that informs the natural history of infection at the single cell level. Here, we review recent reports from human and murine GHV systems that identify striking differences in the immunoglobulin repertoire of infected B cells compared to their uninfected counterparts. Implications for virus biology, GHV-associated cancers, and host immune dysfunction will be discussed.

scholarly journals The Role of Dendritic Cells in Immune Control and Vaccination against γ-Herpesviruses

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1125 ◽  
Author(s):  
Christian Münz
Keyword(s):  
Kaposi Sarcoma ◽  
Immune Control ◽  
Barr Virus ◽  
Persistent Infections ◽  
Cell Responses ◽  
Tumor Virus ◽  
Epstein Barr ◽  
Antigen Presenting ◽  
Adoptive Transfer Therapy

The two human oncogenic γ-herpesviruses, Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV), are prototypic pathogens that are controlled by T cell responses. Despite their ubiquitous distribution, persistent infections and transforming potential, most carriers’ immune systems control them for life. Therefore, they serve as paradigms of how near-perfect cell-mediated immune control can be initiated and maintained for decades. Interestingly, EBV especially quite efficiently avoids dendritic cell (DC) activation, and little evidence exists that these most potent antigen-presenting cells of the human body are involved in the priming of immune control against this tumor virus. However, DCs can be harnessed therapeutically to expand virus-specific T cells for adoptive transfer therapy of patients with virus-associated malignancies and are also currently explored for vaccinations. Unfortunately, despite 55 and 25 years of research on EBV and KSHV, respectively, the priming of their immune control that belongs to the most robust and durable immune responses in humans still remains unclear.

Inhibition of NF-κB induces apoptosis of KSHV-infected primary effusion lymphoma cells

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2537-2542 ◽  
Author(s):  
Shannon A. Keller ◽  
Elaine J. Schattner ◽  
Ethel Cesarman
Keyword(s):  
Primary Effusion Lymphoma ◽  
Leukemia Virus ◽  
Human Lymphocytes ◽  
Kaposi Sarcoma ◽  
Irreversible Inhibitor ◽  
Mobility Shift ◽  
Lymphoma Cells ◽  
Barr Virus ◽  
Human T Cell ◽  
Epstein Barr

Abstract Kaposi sarcoma–associated herpesvirus (KSHV), or human herpervirus 8 (HHV-8), is a γ-herpesvirus that infects human lymphocytes and is associated with primary effusion lymphoma (PEL). Currently, the role of viral infection in the transformation of PEL cells is unknown. One possibility is that KSHV, like the lymphotropic viruses Epstein-Barr virus (EBV) and human T-cell leukemia virus I (HTLV-I), activates the transcription factor NF-κB to promote survival and proliferation of infected lymphocytes. To examine this possibility, we assessed NF-κB activity in KSHV-infected PEL cell lines and primary tumor specimens by electrophoretic mobility shift assay (EMSA). We observed that NF-κB is constitutively activated in all KSHV-infected lymphomas, and consists of 2 predominant complexes, p65/p50 heterodimers and p50/p50 homodimers. Inhibition experiments demonstrated that Bay 11-7082, an irreversible inhibitor of IκBα phosphorylation, completely and specifically abrogated the NF-κB/DNA binding in PEL cells. PEL cells treated with Bay 11 demonstrated down-regulation of the NF-κB inducible cytokine interleukin 6 (IL-6), and apoptosis. These results suggest that NF-κB activity is necessary for survival of KSHV-infected lymphoma cells, and that pharmacologic inhibition of NF-κB may be an effective treatment for PEL.

scholarly journals Viral Causes of Lymphoma: The History of Epstein-Barr Virus and Human T-Lymphotropic Virus 1

2017 ◽  
Vol 8 ◽  
pp. 1178122X1773177 ◽  
Author(s):  
Daniel Esau
Keyword(s):  
Epstein Barr Virus ◽  
Human Cancer ◽  
Human Herpesvirus ◽  
Kaposi Sarcoma ◽  
Cancer Type ◽  
Oncogenic Viruses ◽  
T Lymphotropic Virus ◽  
Barr Virus ◽  
History Of ◽  
Epstein Barr

In 1964, Epstein, Barr, and Achong published a report outlining their discovery of viral particles in lymphoblasts isolated from a patient with Burkitt lymphoma. The Epstein-Barr virus (EBV) was the first human cancer virus to be described, and its discovery paved the way for further investigations into the oncogenic potential of viruses. In the decades following the discovery of EBV, multinational research efforts led to the discovery of further viral causes of various human cancers. Lymphomas are perhaps the cancer type that is most closely associated with oncogenic viruses: infection with EBV, human T-lymphotropic virus 1 (HTLV-1), human immunodeficiency virus (HIV), Kaposi sarcoma-associated herpesvirus/human herpesvirus 8, and hepatitis C virus have all been associated with lymphomagenesis. Lymphomas have also played an important role in the history of oncoviruses, as both the first human oncovirus (EBV) and the first human retrovirus (HTLV-1) were discovered through isolates taken from patients with unique lymphoma syndromes. The history of the discovery of these 2 key oncoviruses is presented here, and their impact on further medical research, using the specific example of HIV research, is briefly discussed.

scholarly journals CD21 (Complement Receptor 2) Is the Receptor for Epstein-Barr Virus Entry into T Cells

2020 ◽  
Vol 94 (11) ◽  
Author(s):  
Nicholas A. Smith ◽  
Carrie B. Coleman ◽  
Benjamin E. Gewurz ◽  
Rosemary Rochford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Neutralizing Antibody ◽  
Cell Infection ◽  
Viral Glycoprotein ◽  
Barr Virus ◽  
Jurkat T Cell ◽  
Peripheral T Cells ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is associated with a number of T-cell diseases, including some peripheral T-cell lymphomas, hemophagocytic lymphohistiocytosis, and chronic active EBV disease. The tropism of EBV for B cells and epithelial cell infection has been well characterized, but infection of T cells has been minimally explored. We have recently shown that the EBV type 2 (EBV-2) strain has the unique ability to infect mature T cells. Utilizing an ex vivo infection model, we sought to understand the viral glycoprotein and cellular receptor required for EBV-2 infection of T cells. Here, using a neutralizing-antibody assay, we found that viral gp350 and complement receptor 2 (CD21) are required for CD3+ T-cell infection. Using the HB5 anti-CD21 antibody clone but not the Bly-4 anti-CD21 antibody clone, we detected expression of CD21 on both CD4+ and CD8+ T cells, with the highest expression on naive CD4 and CD8+ T-cell subsets. Using CRISPR to knock out CD21, we demonstrated that CD21 is necessary for EBV entry into the Jurkat T-cell line. Together, these results indicate that EBV uses the same viral glycoprotein and cellular receptor for both T- and B-cell infection. IMPORTANCE Epstein-Barr virus (EBV) has a well-described tropism for B cells and epithelial cells. Recently, we described the ability of a second strain of EBV, EBV type 2, to infect mature peripheral T cells. Using a neutralizing antibody assay, we determined that EBV uses the viral glycoprotein gp350 and the cellular protein CD21 to gain entry into mature peripheral T cells. CRISPR-Cas9 deletion of CD21 on the Jurkat T-cell line confirmed that CD21 is required for EBV infection. This study has broad implications, as we have defined a function for CD21 on mature peripheral T cells, i.e., as a receptor for EBV. In addition, the requirement for gp350 for T-cell entry has implications for EBV vaccine studies currently targeting the gp350 glycoprotein to prevent EBV-associated diseases.

scholarly journals The interplay between EBV and KSHV viral products and NF-κB pathway in oncogenesis

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
J. Charostad ◽  
M. Nakhaie ◽  
A. Dehghani ◽  
E. Faghihloo
Keyword(s):  
Transcription Factor ◽  
Epstein Barr Virus ◽  
Kaposi Sarcoma ◽  
Compelling Evidence ◽  
Constitutive Activation ◽  
Barr Virus ◽  
Pathophysiological Process ◽  
Tumor Viruses ◽  
Epstein Barr ◽  
Precise Relationship

Abstract Among the DNA tumor viruses Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV), account for a considerable percentage of virus-associated cancers. Deregulation of transcription factors signaling pathways is one of the most significant oncogenic characteristics of EBV and KSHV. NF-κB is a transcription factor that play a remarkable role in oncogenesis because of its function as a master regulator of a spectrum of genes involved in physiological and pathophysiological process. Constitutive activation of NF-κB is a frequent and well-described event in many human malignancies. Compelling evidence represent EBV and KSHV are capable of targeting different components of NF-κB cascade. Here, we summarized recent findings to clarify the precise relationship between dysregulation of NF-κB and EBV and KSHV-related malignancies. This essay also emphasizes on contribution of various viral products in developing cancer through alteration of NF-κB signaling pathway.

scholarly journals Safety and efficacy of an oncolytic viral strategy using bortezomib with ICE/R in relapsed/refractory HIV-positive lymphomas

2018 ◽  
Vol 2 (24) ◽  
pp. 3618-3626 ◽  
Author(s):  
Erin G. Reid ◽  
David Looney ◽  
Frank Maldarelli ◽  
Ariela Noy ◽  
David Henry ◽  
...  
Keyword(s):  
Viral Load ◽  
Cytidine Deaminase ◽  
Single Agent ◽  
Kaposi Sarcoma ◽  
Proteasome Inhibition ◽  
Maximum Tolerated Dose ◽  
Viral Loads ◽  
Barr Virus ◽  
Epstein Barr ◽  
Dose Levels

Abstract HIV-associated lymphomas (HALs) have high rates of latent infection by gammaherpesviruses (GHVs). We hypothesized that proteasome inhibition would induce lytic activation of GHVs and inhibit HIV infectivity via preservation of cytidine deaminase APOBEC3G, improving lymphoma control. We tested this oncolytic and antiviral strategy by using bortezomib combined with ifosfamide, carboplatin, and etoposide (ICE) alone or with rituximab (ICE/R) in relapsed/refractory HAL. A 3+3 dose-escalation design was used with a 7-day lead-in period of single-agent bortezomib. Bortezomib was administered intravenously on days 1 and 8 of each cycle at 1 of 4 dose levels: 0.7, 1.0, 1.3, or 1.5 mg/m2. ICE began day 8 of cycle 1 and day 1 of subsequent cycles. Rituximab was included on day 1 of cycles 2 to 6 for CD20+ lymphomas. Twenty-three patients were enrolled. The maximum tolerated dose of bortezomib was not reached. Grade 4 toxicities attributable to bortezomib were limited to myelosuppression. Responses occurred in 17 (77%) of 22 patients receiving any protocol therapy. The 1-year overall survival was 57%. After bortezomib alone, both patients with Kaposi sarcoma herpesvirus (KSHV)–positive lymphoma had more than a 1-log increase in KSHV viral load. In 12 patients with Epstein-Barr virus (EBV)–positive lymphoma, median values of EBV viral load increased. Undetectable HIV viremia at baseline in the majority of patients limited evaluation of HIV inhibition. APOBEC3G levels increased in 75% of evaluable patients. Bortezomib combined with ICE/R in patients with relapsed/refractory HAL is feasible with response and survival comparing favorably against previously reported second-line therapies. Changes in GHV viral loads and APOBEC3G levels trended as hypothesized. This trial was registered at www.clinicaltrials.gov as #NCT00598169.

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