EBV-Induced Lymphoproliferation

Abstract SCI-9

The similar genome structures, methods of entry, replication, and egress of herpesviruses suggest a common evolutionary origin dating back about 200 million years. EBV, a gammaherpesvirus, has co-evolved with its human host alone for over 80 million years and has developed a relationship that is seldom detrimental to its host and may even be beneficial. For example, EBV-specific T cells with heterologous specificity may protect against other pathogens. Unlike RNA viruses, the sequence of EBV, including its strong immunogenic epitopes, is remarkably conserved even across geographically separated populations. This underscores the comfortable relationship that EBV has developed with the host immune response, which tightly controls but never eliminates the virus. Rarely, this relationship breaks down resulting in diverse diseases and malignancies with underlying causes that are poorly understood. Is mononucleosis restricted to adolescents because of a too active or an inadequate immune response? Why is post-transplant lymphoma (PTLD) not more common in T cell depleted stem cell recipients? How can EBV-positive malignancies develop in patients who have circulating T cells specific for the viral tumor antigens expressed in those malignancies and who control their general EBV infection? Patients with nasopharyngeal carcinoma (NPC) or EBV-positive lymphoma seldom display an elevated virus load in peripheral blood lymphocytes. To prevent EBV-associated diseases we must understand their root causes, which, in turn, require an understanding of the virus’ complex life cycle that comprises involve four types of latency in B cells and replication in both B cells and mucosal epithelium. Each phase of the life cycle is represented both in normal infected cells and in one or more diseases. For example, virus replication is observed in tonsillar epithelium and in the oral hairy leukoplakias of HIV patients. Virus replication is also indirectly associated with NPC; its development is preceded by elevated antibody titers to the viral lytic cycle antigens despite the fact that NPC cells express only latency proteins. There are four patterns of viral latency and three are observed in tumor cells. Type 1 latency (expression of only two of over 90 viral proteins) is observed in normal circulating B cells, Burkitt’s lymphoma and gastric carcinoma. Type 2 latency is shared by the T, B, and NK lymphomas that occur in immunocompetent individuals. Type 3 latency, the most immunogenic form of latency in which nine latency-associated proteins are expressed, is seen in tonsils, in lymphomas of the immunosuppressed and elderly, and in leiomyosarcoma. Therapies may specifically target the function or immunogenicity of the viral proteins, while prophylaxis, usually by vaccination, aims to prevent them. We will discuss the types of latency observed in EBV-associated lymphoproliferations in the context of immunotherapies that might be used to control them.