scholarly journals Kaposi's Sarcoma-Associated Herpesvirus Oncoprotein K13 Protects against B Cell Receptor-Induced Growth Arrest and Apoptosis through NF- B Activation

2012 ◽  
Vol 87 (4) ◽  
pp. 2242-2252 ◽  
Author(s):  
C. Graham ◽  
H. Matta ◽  
Y. Yang ◽  
H. Yi ◽  
Y. Suo ◽  
...  
Keyword(s):  
B Cell ◽  
Kaposi's Sarcoma ◽  
Growth Arrest ◽  
Kaposi’S Sarcoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

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

2015 ◽  
Vol 89 (14) ◽  
pp. 7248-7261 ◽  
Author(s):  
Lisa Steinbrück ◽  
Montse Gustems ◽  
Stephanie Medele ◽  
Thomas F. Schulz ◽  
Dominik Lutter ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Kaposi's Sarcoma ◽  
Epstein Barr Virus ◽  
Kaposi’S Sarcoma ◽  
Cell Receptor ◽  
Barr Virus ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Epstein Barr ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACTThe human herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are associated with Hodgkin's lymphoma (HL) and Primary effusion lymphomas (PEL), respectively, which are B cell malignancies that originate from germinal center B cells. PEL cells but also a quarter of EBV-positive HL tumor cells do not express the genuine B cell receptor (BCR), a situation incompatible with survival of normal B cells. EBV encodesLMP2A, one of EBV's viral latent membrane proteins, which likely replaces the BCR's survival signaling in HL. Whether KSHV encodes a viral BCR mimic that contributes to oncogenesis is not known because an experimental model of KSHV-mediated B cell transformation is lacking. We addressed this uncertainty with mutant EBVs encoding the KSHV genesK1orK15in lieu ofLMP2Aand infected primary BCR-negative (BCR−) human B cells with them. We confirmed that the survival of BCR–B cells and their proliferation depended on an active LMP2A signal. Like LMP2A, the expression ofK1andK15led to the survival of BCR−B cells prone to apoptosis, supported their proliferation, and regulated a similar set of cellular target genes.K1andK15encoded proteins appear to have noncomplementing, redundant functions in this model, but our findings suggest that both KSHV proteins can replace LMP2A's key activities contributing to the survival, activation and proliferation of BCR–PEL cellsin vivo.IMPORTANCESeveral herpesviruses encode oncogenes that are receptor-like proteins. Often, they are constitutively active providing important functions to the latently infected cells. LMP2A of Epstein-Barr virus (EBV) is such a receptor that mimics an activated B cell receptor, BCR. K1 and K15, related receptors of Kaposi's sarcoma-associated herpesvirus (KSHV) expressed in virus-associated tumors, have less obvious functions. We found in infection experiments that both viral receptors of KSHV can replace LMP2A and deliver functions similar to the endogenous BCR. K1, K15, and LMP2A also control the expression of a related set of cellular genes in primary human B cells, the target cells of EBV and KSHV. The observed phenotypes, as well as the known characteristics of these genes, argue for their contributions to cellular survival, B cell activation, and proliferation. Our findings provide one possible explanation for the tumorigenicity of KSHV, which poses a severe problem in immunocompromised patients.

scholarly journals Induction of B Cell Hyperplasia in Simian Immunodeficiency Virus–Infected Rhesus Macaques with the Simian Homologue of Kaposi's Sarcoma–Associated Herpesvirus

1999 ◽  
Vol 190 (6) ◽  
pp. 827-840 ◽  
Author(s):  
Scott W. Wong ◽  
Eric P. Bergquam ◽  
Ryan M. Swanson ◽  
Felix W. Lee ◽  
Stanley M. Shiigi ◽  
...  
Keyword(s):  
Antibody Response ◽  
B Cell ◽  
Simian Immunodeficiency Virus ◽  
Kaposi's Sarcoma ◽  
Rhesus Macaques ◽  
Kaposi’S Sarcoma ◽  
Lymphoid Tissues ◽  
Immunodeficiency Virus ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

A simian homologue of Kaposi's sarcoma–associated herpesvirus (KSHV), the eighth human herpesvirus (HHV8), was isolated from a simian immunodeficiency virus (SIV)-infected rhesus macaque (Macaca mulatta) that developed a multicentric lymphoproliferative disorder (LPD). This simian rhadinovirus is genetically similar to a recently described rhesus rhadinovirus (RRV) (Desrosiers, R.C., V.G. Sasseville, S.C. Czajak, X. Zhang, K.G. Mansfield, A. Kaur, R.P. Johnson, A.A. Lackner, and J.U. Jung. 1997. J. Virol. 71:9764–9769) and is designated RRV 17577. RRV 17577 was experimentally inoculated into rhesus macaques with and without SIVmac239 infection to determine if RRV played a role in development of the LPD observed in the index case. In contrast to control animals inoculated with SIVmac239 or RRV alone, two animals coinfected with SIVmac239 and RRV 17577 developed hyperplastic LPD resembling the multicentric plasma cell variant of Castleman's disease, characterized by persistent angiofollicular lymphadenopathy, hepatomegaly, splenomegaly, and hypergammaglobulinemia. Hypergammaglobulinemia was associated with severe immune-mediated hemolytic anemia in one RRV/SIV-infected macaque. Both RRV/SIV-infected macaques exhibited persistent RRV viremia with little or no RRV-specific antibody response. The macaques inoculated with RRV alone displayed transient viremia followed by a vigorous anti-RRV antibody response and lacked evidence of LPD in peripheral blood and lymph nodes. Infectious RRV and RRV DNA were present in hyperplastic lymphoid tissues of the RRV/SIV-infected macaques, suggesting that lymphoid hyperplasia is associated with the high levels of replication. Thus, experimental RRV 17577 infection of SIV-infected rhesus macaques induces some of the hyperplastic B cell LPDs manifested in AIDS patients coinfected with KSHV.

scholarly journals Efficient Infection of a Human B Cell Line with Cell-Free Kaposi's Sarcoma-Associated Herpesvirus

2013 ◽  
Vol 88 (3) ◽  
pp. 1748-1757 ◽  
Author(s):  
S. J. Dollery ◽  
R. J. Santiago-Crespo ◽  
L. Kardava ◽  
S. Moir ◽  
E. A. Berger
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
Human B Cell

scholarly journals Role of the Kaposi's Sarcoma-Associated Herpesvirus K15 SH3 Binding Site in Inflammatory Signaling and B-Cell Activation

2010 ◽  
Vol 84 (16) ◽  
pp. 8231-8240 ◽  
Author(s):  
Marcel Pietrek ◽  
Melanie M. Brinkmann ◽  
Ilona Glowacka ◽  
Anette Enlund ◽  
Anika Hävemeier ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
B Cell ◽  
Binding Site ◽  
Kaposi's Sarcoma ◽  
Cell Activation ◽  
Kaposi’S Sarcoma ◽  
Binding Motif ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT The Kaposi's sarcoma-associated herpesvirus (KSHV) contains several open reading frames (ORFs) that encode proteins capable of initiating and modulating cellular signaling pathways. Among them is ORF K15, encoding a 12-transmembrane-spanning protein with a cytoplasmic C-terminal domain. Through conserved binding motifs, such as Src homology 2 (SH2) and SH3 binding sites, K15 interacts with cellular proteins, activates the NF-κB, MEK/Erk, and Jun N-terminal protein kinase (JNK) pathways, and induces the expression of several inflammatory and angiogenic genes. In this study, we investigated the role of an SH3 domain binding site centered on a PPLP motif in K15. We screened libraries of cellular SH3 domains to identify signaling molecules interacting with the KSHV PPLP motif. We found its affinities for two Src kinase family members, Lyn and Hck, to exceed those of other viral proteins. While the SH2 binding motif YEEV is essential for the inflammatory response induced by KSHV K15, recruitment of Lyn and Hck to the K15 PPLP motif seems to be dispensable for this inflammatory response. However, the PPLP motif is essential for the decrease in B-cell receptor-mediated signaling induced by K15, as measured by calcium mobilization assays.

scholarly journals Kv1.3 induced hyperpolarisation and Cav3.2-mediated calcium entry are required for efficient Kaposi’s sarcoma-associated herpesvirus lytic replication

2021 ◽  
Author(s):  
Holli Carden ◽  
Mark L. Dallas ◽  
David J. Hughes ◽  
Jonathan D. Lippiat ◽  
Jamel Mankouri ◽  
...  
Keyword(s):  
B Cell ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Lytic Replication ◽  
Host Factors ◽  
Transcription Activator ◽  
Intracellular Ca ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
First Time

AbstractUnderstanding the host factors critical for Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication can identify new targets for therapeutic intervention. Using pharmacological and genetic silencing approaches, we reveal for the first time that KSHV requires a B cell expressed voltage-gated K+ channel, Kv1.3, to enhance lytic replication. We show that the KSHV replication and transcription activator (RTA) protein upregulates Kv1.3 expression, leading to enhanced K+ channel activity and hyperpolarisation of the B cell membrane. Enhanced Kv1.3 activity then promotes intracellular Ca2+ influx through Cav3.2, a T-type Ca2+ channel, leading to the Ca2+ driven nuclear localisation of NFAT and the subsequent NFAT1-responsive gene expression. Importantly, KSHV lytic replication and infectious virion production could be inhibited by both Kv1.3 and Cav3.2 blockers or through Kv1.3 silencing. These findings provide new mechanistic insight into the essential role of host ion channels during KSHV infection and highlight Kv1.3 and Cav3.2 as new druggable host factors that are key to the successful completion of KSHV lytic replication.

scholarly journals The K1 Protein of Kaposi's Sarcoma-Associated Herpesvirus Activates the Akt Signaling Pathway

2004 ◽  
Vol 78 (4) ◽  
pp. 1918-1927 ◽  
Author(s):  
Christine C. Tomlinson ◽  
Blossom Damania
Keyword(s):  
Kaposi's Sarcoma ◽  
Cell Cycle Progression ◽  
B Lymphocyte ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Cellular Transformation ◽  
Cell Receptor ◽  
Focus Formation ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) has been implicated in Kaposi's sarcoma, as well as in primary effusion lymphoma and multicentric Castleman's disease. The K1 protein of KSHV has been shown to induce cellular transformation and focus formation and to deregulate B-lymphocyte signaling pathways by functionally mimicking the activated B-cell receptor complex. Here we show that expression of K1 in B lymphocytes targets the phosphatidylinositol-3 kinase pathway, leading to the activation of the Akt kinase and the inhibition of the phosphatase PTEN. We also demonstrate that activation of Akt by the K1 protein leads to the phosphorylation and inhibition of members of the forkhead (FKHR) transcription factor family, which are key regulators of cell cycle progression and apoptosis. We demonstrate that K1 can inhibit apoptosis induced by the FKHR proteins and by stimulation of the Fas receptor. Our observations suggest that the K1 viral protein promotes cell survival pathways and may contribute to KSHV pathogenesis by preventing virally infected cells from undergoing apoptosis prematurely.

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