Epstein-Barr Virus

In the century preceding the discovery of Epstein-Barr virus (EBV), physicians speculated that a common clinical syndrome characterized by fever, tonsillar adenopathy, splenomegaly, and mononuclear leukocytosis termed glandular fever was caused by a pathogen (1). In 1920, the name infectious mononucleosis (IM) was introduced by Thomas P. Sprunt and Frank A. Evans to characterize this syndrome (2). Three years later, Hal Downey and C.A. McKinlay described the now-classic atypical lymphocyte as a common feature of this disease (3), and in 1932 John Rodman Paul and Walls Willard Bunnell demonstrated high titers of spontaneously occurring heterophile antibodies in the sera of patients with IM (4), ensuring more accurate diagnosis. In 1961, the British surgeon Denis P. Burkitt gave the first account outside of Africa of “The Commonest Children's Cancer in Tropical Africa” at Middlesex Hospital London, detailing the geographic relationship between Burkitt's lymphoma (BL) and conditions of temperature, altitude, and rainfall associated with development of Plasmodium falciparum malaria (5, 6). M. Anthony Epstein, who was in the audience, became intrigued by the idea that a biological agent might be involved in the etiology of BL, and in 1964, the Epstein laboratory analyzed BL biopsy samples by thin-section electron microscopy and discovered a new, large, icosahedral herpesvirus that could be directly reactivated from in vitro–grown BL cells (7). These initial findings were reported in The Lancet, and the virus was named after Epstein and his graduate student Yvonne Barr (8). Shortly thereafter, two independent groups (9, 10) demonstrated the ability of EBV to transform primary human B lymphocytes into permanently growing lymphoblastoid cell lines (LCLs), providing the first concrete evidence of the ability of EBV to promote human cancer. In 1968, Gertrude Henle and Werner Henle made two further critical observations: (1) that EBV seroconversion occurred during the course of acute IM (AIM) in a laboratory technician (9) and (2) that EBV-carrying LCLs spontaneously formed from a peripheral blood leukocyte culture obtained during the acute phase of the technician's illness. The Henles confirmed their observations through study of sera provided by James Corson Niederman and Robert W. McCollum, who collected blood from incoming Yale freshmen and later from individuals who developed AIM. This study and others demonstrated EBV-specific antibodies in the sera of the students who developed AIM, confirming the etiologic association between EBV and AIM (11).