ABSTRACT
Epstein-Barr virus (EBV) is a gamma herpesvirus that persists in the body throughout life. For entry into B cells, gp350 on the viral envelope binds to a complement receptor, CD21 (CR2), on the surface of the host cell. Another envelope glycoprotein, gp42, is responsible for fusion between the virus envelope and the B-cell membrane. EBV can also infect epithelial cells but entry into the cell is gp42 independent. EBV-infected cells can exist in two states. In lytic replication, the resultant virions have a linear DNA genome. In latency, the viral genome is a circular episome, there is limited gene expression and no infectious particle production; there are different patterns of EBV latent gene expression, each of which are associated with various neoplasms.
Spread of the infection is usually through intimate contact with an uninfected person often through kissing and, in children, by fingers contaminated with saliva and other close contact. Globally, most adults are infected with EBV (95–98%). In developing countries, most children become infected as young children. In developed countries, acquisition of EBV is delayed in many individuals until later in life.
During primary infection, the virus probably infects pharyngeal squamous epithelial cells followed by infection of B cells in transit through the tonsils. In adolescents and young adults, about 50% of individuals develop infectious mononucleosis, the symptoms of which are attributable to the intense immunologic response to polyclonally activated B cells mounted by CD8+ T cells. After recovery, the virus remains latent in resting long-lived memory B cells with occasional reactivation into a lytic cycle producing virions shed in saliva and transmissible to a new host. Patients with infectious mononucleosis have pharyngitis, pyrexia, and cervical lymph node and tonsillar enlargement. Diagnosis is usually confirmed by tests for atypical lymphocytes and heterophile antibodies.
The immune response starts as EBV penetrates the oral mucosal epithelium to infect B cells. Intraepithelial lymphocytes including natural killer (NK) cells, invariant NK T (iNKT) cells and γδ T cells are key components of the innate immune response against EBV. IgM antibody to virus capsid antigen (VCA) is the first to appear followed by IgG. Antibodies to the latency antigens, for example, Epstein-Barr nuclear antigen (EBNA), are seen later. Heterophile antibodies are directed against horse, sheep and ox glycolipid antigens on red blood cells. Cytotoxic CD8+ T cells are the cells that control EBV infection.
The many strategies that help EBV to evade the immune system include switching off the expression of EBNA in resting B memory cells; shedding gp42, which binds to MHC class II/peptide complexes and inhibits CD4+ T cell activity; an EBV late protein, BCRF1, is an immunomodulator that inhibits T helper 1 (Th1) cell activity and hence cytolytic CD8+ T cells.
Apart from infectious mononucleosis, individuals with a genetic pre-disposition can develop X-linked lymphoproliferative disease (XLPD) or chronic active EBV. The virus is also associated with neoplastic diseases. These include B-cell malignancies, Burkitt lymphoma and lymphoproliferative disease, and non-B cell malignancies, nasopharyngeal and gastric carcinomas (both of epithelial origin), Hodgkin lymphoma, T- and NK-cell lymphomas.
There is no EBV vaccine. Vaccines targeting gp350 have already been trialed (phase I and phase I/II) and shown to be safe, protecting against symptoms of infectious mononucleosis but not asymptomatic EBV infection. A proposed alternative approach is to induce potent T-cell responses to control primary infection, reduce the viral load and potentially reduce the risk of EBV-induced malignancy. A phase I trial has been completed in Australia with a single EBNA3 epitope. To generate a broad-based cytotoxic T-cell response, a vaccine containing multiple EBV epitopes is necessary.
