Active lytic infection of human primary tonsillar B cells by KSHV and its noncytolytic control by activated CD4+ T cells

Myoung, Jinjong; Ganem, Don

doi:10.1172/jci43755

Cited by 55 publications

(73 citation statements)

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“…In vitro studies of KSHV-infected tonsillar B cells have shown that activated CD4 ϩ T cells can inhibit viral replication in these cells, albeit by an MHC-independent mechanism. 18 Recently, it has been found that vIRF3 can inhibit promoter activity of the class II transactivator (CIITA), the master regulator of class II and other gene expression involved in the class II presentation pathway. Ectopic expression of vIRF3 decreased surface class II expression in B cells and small interfering RNA knockdown of vIRF3 in PELs increased class II expression.…”

Section: Introductionmentioning

confidence: 99%

T-cell immunity to Kaposi sarcoma–associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells

Sabbah

Jagne

Zuo

et al. 2012

Blood

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T-cell immunity is important for controlling Kaposi sarcoma-associated herpesvirus (KSHV) diseases IntroductionKaposi sarcoma-associated herpesvirus (KSHV) is a lymphotropic human herpesvirus with oncogenic potential. KSHV infects endothelial and B cells where it can cause malignancies of these cell types, namely, Kaposi sarcoma (KS) and primary effusion lymphoma (PEL), respectively, 1 and it is associated with the B-cell pathology multicentric Castleman disease (MCD). The HIV epidemic has made these diseases significantly more prevalent, with KS being the most frequently reported HIV-associated malignancy.An important finding from studying KS patients either with HIV, or those immunosuppressed after solid organ transplantation, is that this malignancy can resolve on restoration of immune function through the administration of highly active antiretroviral therapy (HAART) 2 or relaxation of immunosuppression, 3 respectively. These findings and the increased incidence of PEL and MCD in HIV patients 4 suggest that T-cell immunity is critical for control of KSHV infection and disease. Potential immune targets in KS include the latent antigens, namely, the genome maintenance protein LANA that is expressed in all infected cells and malignancies, the viral cyclin vCyclin, the antiapoptotic multifunctional protein vFLIP, and Kaposin. PELs and infected cells in MCD also express at least 2 other proteins, the viral IL-6 and the immunomodulatory and antiapoptotic protein vIRF3.Relatively low T-cell responses to LANA and Kaposin have been described in healthy immunocompetent donors; 5,6 however, most studies have been undertaken using donors with a disrupted immune system or in disease settings, focusing on responses to LANA and Kaposin. Thus, HIV-infected patients on HAART who control KSHV have been found to make T-cell responses to LANA, MCD patients make responses comparable to HIV patients on HAART, but patients with KS disease have very weak or no detectable responses. [7][8][9][10][11] The administration of HAART to HIVassociated KS patients has been associated with the detection and increase in KSHV-specific responses over time. 2,12 Little is known, however, about the size of responses made to the potential tumor antigens vFLIP or vCyclin in healthy donors or patients with disease.How T-cell control is exercised over KSHV-associated malignancies is unclear, particularly in view of the immune evasion mechanisms used by the virus. Thus, LANA encodes an extensive acidic repeat sequence that inhibits efficient synthesis and proteasomal degradation of itself. 13 This strategy, also used by the Epstein-Barr virus (EBV) homolog EBNA1, 14 limits the supply of peptides for presentation to CD8 ϩ T cells. 15 KSHV-specific T-cell killing of infected endothelial cells has not been tested; however, such in vitro infected cells transiently express K5 16 that functions to down-regulate surface HLA class I and other costimulatory molecules. No studies have been performed on the ability of T cells to recognize KSHV-infected cells fro...

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Section: Introductionmentioning

confidence: 99%

T-cell immunity to Kaposi sarcoma–associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells

Sabbah

Jagne

Zuo

et al. 2012

Blood

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“…In contrast, the lack of B cell systems available for the study of KSHV in vitro and in vivo has hampered our understanding of the natural life cycle of KSHV in B cells and of KSHVinduced B cell lymphoproliferations. The JCI has now published three papers (2)(3)(4) that reveal provocative findings regarding KSHV and B cell infection and function.…”

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confidence: 99%

“…EBV enters tonsillar B cells via the CD21 receptor and steers the differentiation of pregerminal naive B lymphocytes toward memory cells by way of viral latent transcripts. The presence of KSHV in saliva (5) and in tonsillar and peripheral CD19 + B cells (6) and the inefficient in vitro infection of primary nonstimulated B lymphocytes from PBMCs prompted the groups of Don Ganem (2) and Dean Kedes (3) to utilize primary tonsillar explants to study KSHV infection ex vivo. Previously, efficient productive or lytic infection of IL-4 and CD40 ligand-activated PBMC-derived B lymphocytes and infection of B lymphocytes from tonsils were demonstrated (7).…”

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Unraveling virus-induced lymphomagenesis

Boshoff

2011

J. Clin. Invest.

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“…Kaposi's sarcomaassociated herpesvirus (KSHV) is a γ2 herpesvirus and the causative agent of Kaposi's sarcoma (KS), as well as two B-cell malignancies, multicentric Castleman's disease (MCD) (297) and primary effusion lymphoma (PEL) (reviewed in (46)). KSHV infects endothelial cells, but can also establish latency and replicate in T and B lymphocytes (123,206,220,221,257). …”

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confidence: 99%

Role of RRV ORF52 in Virion Maturation

Anderson¹

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Rhesus monkey rhadinovirus (RRV) is a close relative of the human pathogen, Kaposi's Sarcoma-Associated Herpesvirus (KSHV). Primary infection with KSHV in culture is highly inefficient and it predominantly adopts a latent phenotype, expressing only a minimal number of viral genes and producing no progeny virions. This contrasts with RRV in culture, which replicates to high viral titer and produces abundant progeny virions, making it a useful model to study gammaherpesvirus lytic replication, virion structure, and the potential roles of tegument proteins in the biology of gammaherpesviruses. Initial work in our laboratory determined that the RRV virion was composed of 33 virally encoded proteins. Of these, 17 are tegument proteins, five of which are unique to the gammaherpesvirus subfamily. ORF52 is one of these five gammaherpesvirus specific tegument proteins and is the focus of this dissertation. This protein is highly abundant within the virion (approximately 1000 copies per particle) and it is closely associated with the capsid. Our results describe a critical role for ORF52 in the cytoplasmic-based later stages of virion morphogenesis. Without ORF52, capsids fail to undergo tegumentation, which is necessary for final envelopment and production of fully infectious virions. In a later section of this dissertation, we also describe preliminary data proposing that ORF52 may play a direct or indirect role in virion transport through interaction with cellular microtubules.iii ACKNOWLEDGEMENTS I grew up in a small, blue-collar, southern Illinois town where most people stay local and focus on getting by day-to-day, not on things like big cities and advanced degrees. I didn't even know what "graduate school" was until several years into my undergraduate education in Chicago, which, by the way, took me 9 years to complete because I worked full-time and went to school off-and-on and part-time when time and money permitted. The reason I share this is because I didn't get here alone, I didn't even know where "here" was and if I'm honest, I don't think I ever really believed I would earn a PhD, because where I'm from, things like that just don't happen to people like me. There truly are so many people I am honored to thank for helping, and supporting, me at various points in this long, wonderful, horrible, amazing, and trying journey that has been the last 10 years of my life, 7 of those at UVa.

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Active lytic infection of human primary tonsillar B cells by KSHV and its noncytolytic control by activated CD4+ T cells

Cited by 55 publications

References 62 publications

T-cell immunity to Kaposi sarcoma–associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells

T-cell immunity to Kaposi sarcoma–associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells

Unraveling virus-induced lymphomagenesis

Role of RRV ORF52 in Virion Maturation

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