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The three subfamilies of herpesviruses (alphaherpesviruses, betaherpesviruses, and gammaherpesviruses) appear to share a unique mechanism for the maturation and egress of virions, mediated by several budding and fusion processes of various organelle membranes during replication, which prevents cellular membrane disruption. Newly synthesized viral DNA is packaged into capsids within the nucleus, which are subsequently released into the cytoplasm via sequential fusion (primary envelopment) and budding through the inner and outer nuclear membranes. Maturation concludes with tegumentation and the secondary envelopment of nucleocapsids, which are mediated by budding into various cell organelles. Intracellular compartments containing mature virions are transported to the plasma membrane via host vesicular trafficking machinery, where they fuse with the plasma membrane to extracellularly release mature virions. The entire process of viral maturation is orchestrated by sequential interactions between viral proteins and intracellular membranes. Compared with other herpesvirus subfamilies, the mechanisms of gammaherpesvirus maturation and egress remain poorly understood. This review summarizes the major findings, including recently updated information of the molecular mechanism underlying the maturation and egress process of the Epstein–Barr virus, a ubiquitous human gammaherpesvirus subfamily member that infects most of the population worldwide and is associated with a number of human malignancies. [ABSTRACT FROM AUTHOR]

The ubiquitous Epstein-Barr virus (EBV) is associated with several human tumors, which include lymphoid and epithelial malignancies. It is known that EBV persistently infects the memory B cell pool of healthy individuals by activating growth and survival signaling pathways that can contribute to B cell lymphomagenesis. Although the monoclonal proliferation of EBV-infected cells can be observed in epithelial tumors, such as nasopharyngeal carcinoma and EBV-associated gastric carcinoma, the precise role of EBV in the carcinogenic progress is not fully understood. This review features characteristics and current understanding of EBV-associated gastric carcinoma. EBV-associated gastric carcinoma comprises almost 10% of all gastric carcinoma cases and expresses restricted EBV latent genes (Latency I). Firstly, definition, epidemiology, and clinical features are discussed. Then, the route of infection and carcinogenic role of viral genes are presented. Of particular interest, the association with frequent genomic CpG methylation and role of miRNA for carcinogenesis are topically discussed. Finally, the possibility of therapies targeting EBV-associated gastric carcinoma is proposed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A droplet digital PCR-based screening method was established to assess the EBV infection status in the GC specimens, which was validated through complete correlation with a conventional EBER1 in situ hybridization assay [12]. EBV establishes latent infection in squamous cell carcinoma cell lines, suggesting that it can be used as an in vitro model to investigate the role of EBV in the development of uncharacterized oral squamous cell carcinoma [6]. Another study using microscopic approaches provided further insights into the EBV lifecycle by demonstrating that EBV exploits the host secretion pathway for the release of progeny virions into the extracellular milieu [8]. [Extracted from the article]

Herpesvirus egress mechanisms are strongly associated with intracellular compartment remodeling processes. Previously, we and other groups have described that intracellular compartments derived from the Golgi apparatus are the maturation sites of Epstein-Barr virus (EBV) virions. However, the mechanism by which these virions are released from the host cell to the extracellular milieu is poorly understood. Here, I adapted two independent induction systems of the EBV lytic cycle in vitro, in the context of Rab GTPase silencing, to characterize the EBV release pathway. Immunofluorescence staining revealed that p350/220, the major EBV glycoprotein, partially co-localized with three Rab GTPases: Rab8a, Rab10, and Rab11a. Furthermore, the knockdown of these Rab GTPases promoted the intracellular accumulation of viral structural proteins by inhibiting its distribution to the plasma membrane. Finally, the knockdown of the Rab8a, Rab10, and Rab11a proteins suppressed the release of EBV infectious virions. Taken together, these findings support the hypothesis that mature EBV virions are released from infected cells to the extracellular milieu via the secretory pathway, as well as providing new insights into the EBV life cycle. [ABSTRACT FROM AUTHOR]

Previous investigations proposed a link between the Epstein-Barr virus (EBV) and lung cancer (LC), but the results are highly controversial largely due to the insufficient sample size and the inherent limitation of the traditional viral screening methods such as PCR. Unlike PCR, current next-generation sequencing (NGS) utilizes an unbiased method for the global assessment of all exogenous agents within a cancer sample with high sensitivity and specificity. In our current study, we aim to resolve this long-standing controversy by utilizing our unbiased NGS-based informatics approaches in conjunction with traditional molecular methods to investigate the role of EBV in a total of 1127 LC. In situ hybridization analysis of 110 LC and 10 normal lung samples detected EBV transcripts in 3 LC samples. Comprehensive virome analyses of RNA sequencing (RNA-seq) data sets from 1017 LC and 110 paired adjacent normal lung specimens revealed EBV transcripts in three lung squamous cell carcinoma and one lung adenocarcinoma samples. In the sample with the highest EBV coverage, transcripts from the BamHI A region accounted for the majority of EBV reads. Expression of EBNA-1, LMP-1 and LMP-2 was observed. A number of viral circular RNA candidates were also detected. Thus, we for the first time revealed a type II latency-like viral transcriptome in the setting of LC in vivo. The high-level expression of viral BamHI A transcripts in LC suggests a functional role of these transcripts, likely as long non-coding RNA. Analyses of cellular gene expression and stained tissue sections indicated an increased immune cell infiltration in the sample expressing high levels of EBV transcripts compared to samples expressing low EBV transcripts. Increased level of immune checkpoint blockade factors was also detected in the sample with higher levels of EBV transcripts, indicating an induced immune tolerance. Lastly, inhibition of immune pathways and activation of oncogenic pathways were detected in the sample with high EBV transcripts compared to the EBV-low LC indicating the direct regulation of cancer pathways by EBV. Taken together, our data support the notion that EBV likely plays a pathological role in a subset of LC. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs), including exosomes and microvesicles, are evolutionarily conserved phospholidpid membrane-bound entities secreted from most eukaryotic cell types. They carry bioactive cargos such as protein and nucleic acids derived from their cells of origin. Over the past 10 years, they have been attracting increased attention in many fields of life science, representing a new route for intercellular communication. In this review article, we will discuss the current knowledge of both normal and virally modified EVs in the regulation of Epstein-Barr virus (EBV)'s life cycle and its associated pathogenesis. [ABSTRACT FROM AUTHOR]

Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is associated with various malignancies in B lymphocytes and epithelial cells. EBV encodes 49 microRNAs in two separated regions, termed the BART and BHRF1 loci. Although accumulating evidence demonstrates that EBV infection regulates the profile of microRNAs in the cells, little is known about the microRNAs in exosomes released from infected cells. Here, we characterized the expression profile of intracellular and exosomal microRNAs in EBV-negative, and two related EBV-infected Burkitt lymphoma cell lines having type I and type III latency by next-generation sequencing. We found that the biogenesis of exosomes is upregulated in type III latently infected cells compared with EBV-negative and type I latently infected cells. We also observed that viral and several specific host microRNAs were predominantly incorporated in the exosomes released from the cells in type III latency. We confirmed that multiple viral microRNAs were transferred to the epithelial cells cocultured with EBV-infected B cells. Our findings indicate that EBV infection, in particular in type III latency, modulates the biogenesis of exosomes and the profile of exosomal microRNAs, potentially contributing to phenotypic changes in cells receiving these exosomes. [ABSTRACT FROM AUTHOR]