even fatal IM. This extensive morbidity might be decreased by appropriate immunotherapy, but there is at present no effective antiviral therapy.

In most cases EBV establishes latency in the B-lymphocytes. However, EBV is associated with a variety of aplastic diseases, including 80 percent of AIDS-related lymphomas. Among post-transplant proliferative disorders, anywhere from 25 percent to 100 percent (depending on organ) occur in patients who are having a primary EBV infection. Similarly, there are many similarities between IM and Hodgkin’s disease—patients with a history of IM are 2 to 3 times more likely to develop Hodgkin’s lymphoma, and 70 percent of Hodgkin’s-like lymphocytes are EBV-positive. EBV is also associated with Burkitt’s lymphoma, which is relatively rare in the United States but is endemic in Africa. EBV is associated with the vast majority of nasopharyngeal carcinoma, which occurs when the virus is reactivated in mucosal lymphocytes and infects epithelial cells, which develop abnormalities and rapidly becomes dysplasia or carcinoma in situ. EBV is now being described in an increasing number of T-cell lymphomas, a significant proportion of Hodgkin’s disease, and in discrete substantive gastric carcinomas. Other related diseases include hairy leukoplakia, which was originally described in AIDS patients.

Pathobiology. EBV can establish both permissive infection in epithelial cells and lymphocytes and latent, nonpermissive transforming infections in lymphocytes. Pathogenesis involves introduction of the virus into the oral epithelial cells, which are usually permissive to viral infection, and virus is then secreted into the saliva. Secondarily to this epithelial infection, virus enters the B-lymphocyte, where it circularizes, forming an extra chromosomal episome in the nucleus. One week after the initial infection, as many as 5 percent to 20 percent of peripheral blood lymphocytes are infected with EBV, including a wide variety of cell types: B-lymphocytes, Reed-Sternberg-like cells, plasmacytoid cells, and even a small percentage of T-lymphocytes. This is basically a latent infection: most of these cells do not make viruses but instead begin to express viral gene products that are associated with the process of cellular transformation. Many of these gene products are very potent targets of cytotoxic T-lymphocytes (CTLs), which must be generated to control the infection and the transformed lymphocytes. In the absence of T-cell response, these lymphocytes grow uncontrolled and eventually develop into a lymphoma.

Viral Genome. Analysis of the viral genome can distinguish latent from replicative infection and is informative in other ways. Like HSV, the EBV genome is a double-stranded DNA molecule with variants, but with a simpler structure. It is about 190 kB long, but instead of inverted repeats, it has multiple copies of a 500-base-pair direct repeat at each end of the genome. Variants are highly heterogenous, with anywhere from 1 to 20 copies of the terminal fragments at either end of the genome. This assay was able to distinguish between the variant form from the larger episomal form, but it also revealed that (within each cell) each of the up to 100 copies of the EBV episome was identical with regard to the number of terminal repeats. This also suggested that every cell within a tumor would be identical, from which researchers deduced that the