*3.1. Characteristics of the Infection Mechanism in EBV*

EBV is a member of the family of herpes viruses. It is a double-stranded DNA virus, and the nomenclature of EBV is human herpes virus 4 (HHV-4). EBV was originally isolated from culture medium of Burkitt tumor cells [30], and EBV was an etiological agent for infectious mononucleosis or nasopharyngeal carcinoma in China [31]. Clinical issues of concern are the activation of EBV in specific conditions; for example, the reactivation of EBV was observed in the early infection phase of human immunodeficiency virus (HIV), and EBV reactivation within six months was observed before HIV seroconversion [32]. The reactivation of EBV has also been frequently detected under immunosuppressive conditions. The management of EBV reactivation in cases of stem cell transplantation under intensive immunosuppression is a serious issue [33].

In the field of rheumatology, the involvement of EBV in methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a considerable problem in the era of molecular-targeted therapy for RA [34]. In addition, chronic active EBV (CAEBV) infection [35] was classified as a new entity in the revised version of World Health Organization (WHO) criteria, in which EBV can infect not only B cells but also T cells and natural killer cells, resulting in a poor prognosis. There is a specific mode of infection in EBV that includes a latent and lytic infection phase during the EBV life cycle [36]. The latent infection of EBV was usually observed in peripheral blood B cells with the expression of latent membrane protein (LMP), which is associated with B-cell transformation [37]. In addition, the latency of EBV was categorized into four patterns (from 0 to III) based on the host cells' condition [38] with various expression patterns of EB nuclear antigen (EBNA)1 or EB-encoding regions (EBERs). In the latent phase, viral particles are not produced with the expression of non-structural protein in B cells. In contrast, the latent phase was switched to the lytic phase by LMP1 that was induced by BRLF1 [39], and once EBV had entered the lytic cycle, emitted EBV virions infected mucosal epithelial cells of the pharynx or ductal epithelial cells of salivary glands.
