ABSTRACT
Epstein-Barr virus (EBV) has developed a relationship with its human host that allows it to persist throughout the life of the infected individual without pathology. However, disruptions of the highly evolved balance between the virus lytic and latent life cycles and host immune control result in a range of EBV-associated diseases involving B-cells, epithelial cells, T-cells, natural killer (NK) cells, or muscle. In the simplest case, iatrogenic immunosuppression occurring after stem cell or organ transplantation leads to the outgrowth of virus-transformed B-cells resulting in posttransplant lymphoproliferative disease (PTLD) (1). While PTLD clearly results from severe T-cell dysfunction, subtler and less well understood immune defects, such as cytokine imbalance, may also play a role in the etiology of PTLD (2,3). Loss of control of the lytic life cycle of EBV is associated with chronic active EBV (CAEBV) infection and oral hairy leukoplakia in AIDS patients. However, the immunological defects underlying these diseases are not understood, because less is known about the control of the lytic cycle of EBV than of its latent cycle. EBV may also cause disease by subverting the immune response, not directly as do other herpesviruses, but by interaction with the infected cell. For example, the malignant growth of EBVinfected germinal center B-cells in EBV-positive Hodgkin’s disease (HD) occurs in individuals with no known preexisting immunological defect. EBV-infected malignant Hodgkin-Reed-Sternberg (HRS) cells secrete cytokines and chemokines that are inhibitory to the activation and function of cytotoxic T-lymphocytes (CTL) resulting in an ineffective immune response (4). The EBV latent membrane protein 1 (LMP1) that is expressed in EBV-positive HRS cells induces cytokine expression through activation of the NF-jB pathway and may have an important role in this
cytokine activation. However, because EBV-negative HRS cells also secrete inhibitory cytokines, the role of EBV is unclear (5). The cytokines produced by HRS cells are likely the cause of the generalized immune suppression seen in Hodgkin patients and may impede the efficacy of immunotherapies for this disease (6,7). Viral characteristics may also disrupt the virus-host balance, and much research has gone into identifying virological differences that might result in a more virulent virus. However, no clear association between virulence and genetic change has been found (5,8,9). EBVassociated diseases are generally difficult to treat because specific antiviral drugs influence only the lytic cycle (10,11). However, the viral antigens expressed in the involved cells provide target antigens against which immunotherapies and molecularly targeted drugs may be directed. Improved understanding of the defects, virological or immunological, underlying each disorder is key to developing rational and effective treatments. The immunological features of most of the diseases associated with EBV suggest that immunotherapeutic remedies may be appropriate, and it is the focus of this chapter to discuss possible immunological solutions.
