scholarly journals The Role of Lytic Infection for Lymphomagenesis of Human γ-Herpesviruses

2021 ◽  
Vol 11 ◽  
Author(s):  
Christian Münz
Keyword(s):  
Kaposi Sarcoma ◽  
Lytic Replication ◽  
Host Cells ◽  
Paradigm Change ◽  
Oncogenic Viruses ◽  
Lytic Gene ◽  
Barr Virus ◽  
Bona Fide ◽  
Epstein Barr

Epstein Barr virus (EBV) and Kaposi sarcoma associated herpesvirus (KSHV) are two oncogenic human γ-herpesviruses that are each associated with 1-2% of human tumors. They encode bona fide oncogenes that they express during latent infection to amplify their host cells and themselves within these. In contrast, lytic virus particle producing infection has been considered to destroy host cells and might be even induced to therapeutically eliminate EBV and KSHV associated tumors. However, it has become apparent in recent years that early lytic replication supports tumorigenesis by these two human oncogenic viruses. This review will discuss the evidence for this paradigm change and how lytic gene products might condition the microenvironment to facilitate EBV and KSHV associated tumorigenesis.

scholarly journals Tumour viruses and innate immunity

2017 ◽  
Vol 372 (1732) ◽  
pp. 20160267 ◽  
Author(s):  
Sharon E. Hopcraft ◽  
Blossom Damania
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Host Cells ◽  
Oncogenic Viruses ◽  
Barr Virus ◽  
Human T Cell ◽  
Epstein Barr

Host cells sense viral infection through pattern recognition receptors (PRRs), which detect pathogen-associated molecular patterns (PAMPs) and stimulate an innate immune response. PRRs are localized to several different cellular compartments and are stimulated by viral proteins and nucleic acids. PRR activation initiates signal transduction events that ultimately result in an inflammatory response. Human tumour viruses, which include Kaposi's sarcoma-associated herpesvirus, Epstein–Barr virus, human papillomavirus, hepatitis C virus, hepatitis B virus, human T-cell lymphotropic virus type 1 and Merkel cell polyomavirus, are detected by several different PRRs. These viruses engage in a variety of mechanisms to evade the innate immune response, including downregulating PRRs, inhibiting PRR signalling, and disrupting the activation of transcription factors critical for mediating the inflammatory response, among others. This review will describe tumour virus PAMPs and the PRRs responsible for detecting viral infection, PRR signalling pathways, and the mechanisms by which tumour viruses evade the host innate immune system. This article is part of the themed issue ‘Human oncogenic viruses’.

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.

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 New Noncoding Lytic Transcripts Derived from the Epstein-Barr Virus Latency Origin of Replication,oriP, Are Hyperedited, Bind the Paraspeckle Protein, NONO/p54nrb, and Support Viral Lytic Transcription

2015 ◽  
Vol 89 (14) ◽  
pp. 7120-7132 ◽  
Author(s):  
Subing Cao ◽  
Walter Moss ◽  
Tina O'Grady ◽  
Monica Concha ◽  
Michael J. Strong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epstein Barr Virus ◽  
Noncoding Rnas ◽  
Lytic Replication ◽  
Long Noncoding Rnas ◽  
Origin Of Replication ◽  
Lytic Gene ◽  
Barr Virus ◽  
Lytic Gene Expression ◽  
Epstein Barr

ABSTRACTWe have previously shown that the Epstein-Barr virus (EBV) likely encodes hundreds of viral long noncoding RNAs (vlncRNAs) that are expressed during reactivation. Here we show that the EBV latency origin of replication (oriP) is transcribed bi-directionally during reactivation and that both leftward (oriPtLs) and rightward (oriPtRs) transcripts are largely localized in the nucleus. While the oriPtLs are most likely noncoding, at least some of the oriPtRs contain the BCRF1/vIL10 open reading frame. Nonetheless, oriPtR transcripts with long 5′ untranslated regions may partially serve noncoding functions. Both oriPtL and oriPtR transcripts are expressed with late kinetics, and their expression is inhibited by phosphonoacetic acid. RNA sequencing (RNA-seq) analysis showed that oriPtLs and oriPtRs exhibited extensive “hyperediting” at their Family of Repeat (FR) regions. RNA secondary structure prediction revealed that the FR region of both oriPtLs and oriPtRs may form large evolutionarily conserved and thermodynamically stable hairpins. The double-stranded RNA-binding protein and RNA-editing enzyme ADAR was found to bind to oriPtLs, likely facilitating editing of the FR hairpin. Further, the multifunctional paraspeckle protein, NONO, was found to bind to oriPt transcripts, suggesting that oriPts interact with the paraspeckle-based innate antiviral immune pathway. Knockdown and ectopic expression of oriPtLs showed that it contributes to global viral lytic gene expression and viral DNA replication. Together, these results show that these new vlncRNAs interact with cellular innate immune pathways and that they help facilitate progression of the viral lytic cascade.IMPORTANCERecent studies have revealed that the complexity of lytic herpesviral transcriptomes is significantly greater than previously appreciated with hundreds of viral long noncoding RNAs (vlncRNAs) being recently discovered. Work on cellular lncRNAs over the past several years has just begun to give us an initial appreciation for the array of functions they play in complex formation and regulatory processes in the cell. The newly identified herpesvirus lncRNAs are similarly likely to play a variety of different functions, although these functions are likely tailored to specific needs of the viral infection cycles. Here we describe novel transcripts derived from the EBV latency origin of replication. We show that they are hyperedited, that they interact with a relatively newly appreciated antiviral pathway, and that they play a role in facilitating viral lytic gene expression. These investigations are a starting point to unraveling the complex arena of vlncRNA function in herpesvirus lytic replication.

scholarly journals The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA

2015 ◽  
Vol 112 (21) ◽  
pp. 6694-6699 ◽  
Author(s):  
Jan Hellert ◽  
Magdalena Weidner-Glunde ◽  
Joern Krausze ◽  
Heinrich Lünsdorf ◽  
Christiane Ritter ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Epstein Barr Virus ◽  
Kaposi Sarcoma ◽  
Higher Order ◽  
Host Cells ◽  
Nuclear Antigen ◽  
Arbitrary Sequence ◽  
Homologous Proteins ◽  
Barr Virus ◽  
Epstein Barr

Kaposi sarcoma herpesvirus (KSHV) persists as a latent nuclear episome in dividing host cells. This episome is tethered to host chromatin to ensure proper segregation during mitosis. For duplication of the latent genome, the cellular replication machinery is recruited. Both of these functions rely on the constitutively expressed latency-associated nuclear antigen (LANA) of the virus. Here, we report the crystal structure of the KSHV LANA DNA-binding domain (DBD) in complex with its high-affinity viral target DNA, LANA binding site 1 (LBS1), at 2.9 Å resolution. In contrast to homologous proteins such as Epstein-Barr virus nuclear antigen 1 (EBNA-1) of the related γ-herpesvirus Epstein-Barr virus, specific DNA recognition by LANA is highly asymmetric. In addition to solving the crystal structure, we found that apart from the two known LANA binding sites, LBS1 and LBS2, LANA also binds to a novel site, denoted LBS3. All three sites are located in a region of the KSHV terminal repeat subunit previously recognized as a minimal replicator. Moreover, we show that the LANA DBD can coat DNA of arbitrary sequence by virtue of a characteristic lysine patch, which is absent in EBNA-1 of the Epstein-Barr virus. Likely, these higher-order assemblies involve the self-association of LANA into supermolecular spirals. One such spiral assembly was solved as a crystal structure of 3.7 Å resolution in the absence of DNA. On the basis of our data, we propose a model for the controlled nucleation of higher-order LANA oligomers that might contribute to the characteristic subnuclear KSHV microdomains (“LANA speckles”), a hallmark of KSHV latency.

scholarly journals Oncogenic Viral Prevalence in Invasive Vulvar Cancer Specimens From Human Immunodeficiency Virus–Positive and -Negative Women in Botswana

2014 ◽  
Vol 24 (4) ◽  
pp. 758-765 ◽  
Author(s):  
Martha Tesfalul ◽  
Kenneth Simbiri ◽  
Chikoti M. Wheat ◽  
Didintle Motsepe ◽  
Hayley Goldbach ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Squamous Cell ◽  
Cell Cancer ◽  
Kaposi Sarcoma ◽  
Oncogenic Viruses ◽  
Hiv Status ◽  
Barr Virus ◽  
Immunodeficiency Virus ◽  
Viral Testing ◽  
Epstein Barr

ObjectiveThe primary aim of this study was to describe the prevalence of select oncogenic viruses within vulvar squamous cell carcinoma (VSCC) and their association with human immunodeficiency virus (HIV) status in women in Botswana, where the national HIV prevalence is the third highest in the world.MethodsA cross-sectional study of biopsy-confirmed VSCC specimens and corresponding clinical data was conducted in Gaborone, Botswana. Polymerase chain reaction (PCR) and immunohistochemistry (IHC) viral testing were done for Epstein-Barr virus, human papillomavirus (HPV) strains, and Kaposi sarcoma herpesvirus, and PCR viral testing alone was done for John Cunningham virus.ResultsHuman papillomavirus prevalence by PCR was 100% (35/35) among tested samples. Human papillomavirus type 16 was the most prevalent HPV strain (82.9% by PCR, 94.7% by either PCR or IHC). Kaposi sarcoma herpesvirus prevalence by PCR had a significant association with HIV status (P = 0.013), but not by IHC (P = 0.650).ConclusionsThe high burden of HPV, specifically HPV16, in vulvar squamous cell cancer in Botswana suggests a distinct HPV profile that differs from other studied populations, which provides increased motivation for HPV vaccination efforts. Oncogenic viruses Kaposi sarcoma herpesvirus and Epstein-Barr virus were also more prevalent in our study population, although their potential role in vulvar squamous cell cancer pathology is unclear.

scholarly journals The Epstein-Barr Virus BDLF4 Gene Is Required for Efficient Expression of Viral Late Lytic Genes

2015 ◽  
Vol 89 (19) ◽  
pp. 10120-10124 ◽  
Author(s):  
Takahiro Watanabe ◽  
Yohei Narita ◽  
Masahiro Yoshida ◽  
Yoshitaka Sato ◽  
Fumi Goshima ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epstein Barr Virus ◽  
Lytic Replication ◽  
Late Gene ◽  
Late Gene Expression ◽  
Lytic Gene ◽  
Barr Virus ◽  
Efficient Expression ◽  
Epstein Barr ◽  
Lytic Genes

Epstein-Barr virus (EBV) is a gammaherpesvirus, associated with infectious mononucleosis and various types of malignancy. We focused here on the BDLF4 gene of EBV and identified it as a lytic gene, expressed with early kinetics. Viral late gene expression of the BDLF4 knockout strain was severely restricted; this could be restored by an exogenous supply of BDLF4. These results indicate that BDLF4 is important for the EBV lytic replication cycle, especially in late gene expression.

scholarly journals Pathogenic Role of Epstein–Barr Virus in Lung Cancers

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 877
Author(s):  
David Becnel ◽  
Ramsy Abdelghani ◽  
Asuka Nanbo ◽  
Janardhan Avilala ◽  
Jacob Kahn ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Causal Link ◽  
Oncogenic Viruses ◽  
Lung Carcinogenesis ◽  
Future Directions ◽  
Lung Cancers ◽  
Barr Virus ◽  
Total Cancer ◽  
Epstein Barr

Human oncogenic viruses account for at least 12% of total cancer cases worldwide. Epstein–Barr virus (EBV) is the first identified human oncogenic virus and it alone causes ~200,000 cancer cases and ~1.8% of total cancer-related death annually. Over the past 40 years, increasing lines of evidence have supported a causal link between EBV infection and a subgroup of lung cancers (LCs). In this article, we review the current understanding of the EBV-LC association and the etiological role of EBV in lung carcinogenesis. We also discuss the clinical impact of the knowledge gained from previous research, challenges, and future directions in this field. Given the high clinical relevance of EBV-LC association, there is an urgent need for further investigation on this topic.

scholarly journals Initial Characterization of the Epstein–Barr Virus BSRF1 Gene Product

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 285 ◽  
Author(s):  
Yusuke Yanagi ◽  
H. Masud ◽  
Takahiro Watanabe ◽  
Yoshitaka Sato ◽  
Fumi Goshima ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Nk Cell ◽  
Artificial Chromosome ◽  
Immunofluorescence Assay ◽  
Lytic Replication ◽  
Reading Frame ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus

Epstein–Barr virus (EBV) is a ubiquitous virus that causes infectious mononucleosis and several types of cancer, such as Burkitt lymphoma, T/NK-cell lymphoma, and nasopharyngeal carcinoma. As a herpesvirus, it encodes more than 80 genes, many of which have not been characterized. EBV BamHI S rightward reading frame 1 (BSRF1) encodes a tegument protein that, unlike its homologs herpes simplex virus unique long 51 (UL51) and human cytomegalovirus UL71, has not been extensively investigated. To examine the role of BSRF1, we prepared knockout and revertant strains using the bacterial artificial chromosome system. Unexpectedly, the disruption of the gene had little or no effect on EBV lytic replication and the transformation of primary B cells. However, the knockdown of BSRF1 in B95-8 cells decreased progeny production. An immunofluorescence assay revealed that BSRF1 localized to the Golgi apparatus in the cytoplasm, as did its homologs. BSRF1 also associated with BamHI G leftward reading frame 3.5 (BGLF3.5), BamHI B rightward reading frame 2 (BBRF2), and BamHI A leftward reading frame 1 (BALF1), and BALF1 was incorporated into the tegument fraction with BSRF1. Taken together, our results indicate that BSRF1 plays a role in secondary envelopment or virion egress in the cytoplasm, as do its homolog genes.

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