Abstract
Epstein-Barr virus (EBV) infection is closely associated with undifferentiated nasopharyngeal carcinoma (NPC), strongly implicating a role for EBV in NPC pathogenesis; conversely, EBV infection is rarely detected in normal nasopharyngeal epithelial tissues. In general, EBV does not show a strong tropism for infecting human epithelial cells, and EBV infection in oropharyngeal epithelial cells is believed to be lytic in nature. To establish life-long infection in humans, EBV has evolved efficient strategies to infect B cells and hijack their cellular machinery for latent infection. Lytic EBV infection in oropharyngeal epithelial cells, though an infrequent event, is believed to be a major source of infectious EBV particles for salivary transmission. The biological events associated with nasopharyngeal epithelial cells are only beginning to be understood with the advancement of EBV infection methods and the availability of nasopharyngeal epithelial cell models for EBV infection studies. EBV infection in human epithelial cells is a highly inefficient process compared to that in B cells, which express the complement receptor type 2 (CR2) to mediate EBV infection. Although receptor(s) on the epithelial cell surface for EBV infection remain(s) to be identified, EBV infection in epithelial cells could be achieved via the interaction of glycoproteins on the viral envelope with surface integrins on epithelial cells, which might trigger membrane fusion to internalize EBV in cells. Normal nasopharyngeal epithelial cells are not permissive for latent EBV infection, and EBV infection in normal nasopharyngeal epithelial cells usually results in growth arrest. However, genetic alterations in premalignant nasopharyngeal epithelial cells, including p16 deletion and cyclin D1 overexpression, could override the growth inhibitory effect of EBV infection to support stable and latent EBV infection in nasopharyngeal epithelial cells. The EBV episome in NPC is clonal in nature, suggesting that NPC develops from a single EBV-infected nasopharyngeal epithelial cell, and the establishment of persistent and latent EBV infection in premalignant nasopharyngeal epithelium may represent an early and critical event for NPC development.
Highlights
Epstein-Barr virus (EBV) infection is closely associated with undifferentiated nasopharyngeal carcinoma (NPC), strongly implicating a role for EBV in NPC pathogenesis; EBV infection is rarely detected in normal nasopharyngeal epithelial tissues
We review the recent findings related to the mechanisms involved in the entry of EBV and the establishment of stable latent infection of EBV in nasopharyngeal epithelial cells, which has long been postulated as an early event in NPC pathogenesis
We have recently reported that EBV could establish latent infection in telomerase-immortalized nasopharyngeal epithelial cells harboring a p16 deletion or overexpressing cyclin D1/Bmi-1[30,31,32]
Summary
EBV was first discovered by Epstein, Achong, and Barr in 1964 as a herpesvirus in tumor cell lines derived from Burkitt’s lymphoma[1]. EBV infection is associated with other human malignancies, including NPC, Hodgkin’s disease, and gastric carcinoma, as well as lymphoproliferative disorders in immune-compromised patients[4]. In contrast to the transforming property of the virus observed in B cells, EBV infection and the expression of viral genes do not readily transform primary nasopharyngeal epithelial cells into proliferative or immortalized cell lines[4,7,8]. Its role in the pathogenesis of NPC remains to be elucidated, the malignant transformation of EBV-infected nasopharyngeal epithelial cells is believed to be a multi-step process over a long period of time and involve an intricate interplay between EBV genes and host genetic alterations in premalignant nasopharyngeal epithelial cells[8,9,10]. We review the recent findings related to the mechanisms involved in the entry of EBV and the establishment of stable latent infection of EBV in nasopharyngeal epithelial cells, which has long been postulated as an early event in NPC pathogenesis
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