EBV in Humans

EBV

Epstein-Barr virus (EBV), the most ubiquitous human virus, was first identified in Burkitt's lymphoma (BL) in 1964 and was later identified as the first human oncolytic virus. It has been implicated in the pathogenesis of Hodgkin's lymphoma (HL), non-lymphoid neoplasms in post-transplant patients and HIV-infected individuals, malignancies such as nasopharyngeal and gastric cancers, and in adolescents EBV is the leading cause of infectious mononucleosis (IM). EBV is also known as Human Herpesvirus 4 (HHV-4), and its life cycle is similar to other herpesviruses, with incubation and cleavage periods. Viruses in the latent phase exist as circular segments in the nucleus, linked to host genomic chromatin by the EBNA1 viral protein, and viruses in this state express a small fraction of viral genes and noncoding RNAs. During the latent phase, the virus relies on normal cell division processes, including the host DNA replication machinery, to passively replicate its viral genome and spread to daughter cells. EBV is capable of lifelong latency in the human body, and under certain conditions, the virus is able to reactivate and enter a cleavage cycle in which all viral genes are expressed, and the virus can replicate its viral genome and produce infectious offspring, a process that leads to cell death and the release of infectious viruses, which can infect naïve cells in the same host, or spread to new hosts.

EBV Reactivation

The lysis form of EBV infection is required to produce infectious viral particles and is essential for cell-to-cell and host-to-host transmission of the virus. The number of EBV-infected B cells decreases after the use of drugs to inhibit lysis of EBV replication, suggesting that reactivation and replication of EBV may help to replenish the pool of latently infected cells in the infected host. Lytic EBV genes are categorized as IE, early or late lytic genes, and lytic reactivation is mediated by the expression of two viral IE lytic proteins, BZLF1 (Z, ZTA, ZEBRA) and BRLF1 (R, RTA). Z and R encode viral transcription factors that collectively activate each of the early lysis EBV proteins required for replicative lytic forms of EBV viral DNA expression. The early cleavage gene promoter contains cis-acting motifs that bind to Z and/or R. Transcription is activated when bound to Z and/or R proteins. Late cleavage genes encode proteins required for viral particle assembly. The activity of the viral promoters that drive Z and R expression (Zp and Rp, respectively) is mainly regulated by cellular transcription factors. Important biological inducers of B-cell lytic EBV reactivation include B-cell receptor activation and plasma cell differentiation. In addition, remaining stimuli, such as hypoxia, inflammasome induction and DNA damage, can also induce EBV reactivation. In contrast, other cellular transcription factors (ZEB1/2, c-myc, KAP1, and IRF4) promote viral latency.

Figure 1. EBV modulation of the infected cell
(Source: Damania B, et al. 2022)

EBV Symptoms

Primary infection with EBV typically occurs in childhood, with no obvious clinical signs of infection, and when uninfected adolescents are exposed to EBV, approximately 30%-70% will develop IM. For primary infectious mononucleosis, the usual incubation period is 32-49 days, when there are no obvious symptoms. In the acute phase, patients present with a sore throat, headache, cervical lymphadenopathy, fever, fatigue, and in a few cases hepatomegaly, nausea, vomiting, eyelid edema, and rash. A feature of the clinical presentation of IM is the long duration of the disease, with a median acute episode duration of 18 days. Serious complications are rare in the acute phase of primary EBV infection; very few patients may develop airway obstruction due to oropharyngeal inflammation, meningoencephalitis, streptococcal pharyngitis, hemolytic anemia, and thrombocytopenia. When an acute infection moves to the chronic phase, chronic IM can be categorized into two clinical presentations, the first of which involves a gradual return to health, but with persistent recurrent symptoms months to years later. The second pattern is rarer and presents as a persistent "monotypic" disease that continues indefinitely.

EBV and Cancer

EBV is associated with a variety of lymphatic malignancies as well as epithelial cancers such as nasopharyngeal and gastric cancers. EBV is an important factor in these pathologic processes, combining genetic, environmental, immunologic, or infectious factors to lead to cancer development. Different types of cancers are associated with EBV to different degrees; for example, EBV is associated with nasopharyngeal carcinoma, endemic BL, T/NK lymphoma, and HIV-associated primary central nervous system lymphoma in 100% of cases, whereas it is associated with HL, NHL, and gastric cancer in less than 30% of cases. EBV is associated with undifferentiated nasopharyngeal carcinoma (NPC), and some investigators have suggested that persistent infection of genetically aberrant epithelial cells with EBV induces tumorigenic transformation and clonal expansion of infected cells. Other cofactors, such as long-term exposure to environmental carcinogens, contribute to the development of nasopharyngeal carcinoma and can induce a range of somatic genetic changes in epithelial cells. EBV DNA molecules circulating in the blood of NPC patients in the form of naked DNA fragments released from cancer cells into the plasma are considered prognostic biomarkers for nasopharyngeal carcinoma, with potential clinical value in screening, prognosis, and recurrence monitoring.