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critical gene for neoplastic growth. LMP-2 associates with LMP-1 in transformed cells and appears to block activation of the B-lymphocyte by interfering with the signals that would induce antibody synthesis. In doing so, LMP-2 helps to maintain the latent infection.

A last set of EBV genes expressed in infected cells are called Epstein-Barr encoded RNAs (EBERs). They are RNA polymerase-3 transfers, but their function is not yet known. They are not essential for transformation, but they are extremely abundant (50,000 to 1 million copies per infected cell) and very stable. EBERs can be very useful for identifying infected tissues, and because they are not expressed in hairy leukoplakia (a permissive infection) they may be useful in identifying repositories of latent infection.

Levels of Latency. Research on the actual behavior of EBV in each of the associated pathologies has shown that there are actually three levels of latency. Type one latency is a minimal level of expression, characteristic of Burkitt’s lymphoma. Only EBNA-1 and the EBERs are expressed, so the infected cells do not become targets for cytotoxic T-cells. The peripheral blood lymphocytes of normal individuals who have been exposed to EBV also express EBNA-1 and EBERs, and they are also believed to express LMP-2, helping to maintain them in a state of latent infection.

In type two latency, additional genes are expressed. Specifically, LMP-1 and LMP-2, two genes that are regulated by the EBNAs, are expressed in the absence of the EBNAs. In other words, the critical transforming genes are being expressed but not the key CTL targets, which may be important in the development of disease for which this is the characteristic state of latency, including nasopharyngeal carcinoma, Hodgkin’s disease, and T-cell lymphoma.

In type three latency, the entire array of EBV latent genes are expressed, including not only the oncogenes but also EBNAs 2 through 6, which are the key CTL targets, as well as high levels of EBERs whose function is as yet unknown. This type of infection, which is typical of peripheral blood lymphocytes in infectious mononucleosis and most of the cells in post-transplant proliferative disease, should be very amenable to control by the immune system.

In replicative infection, one vital gene called ZEBRA is the replication activator that turns on the expression of the viral replicative antigens (including polymerase and thymidine kinase) and the structural proteins (including the viral caps antigen, or VCA, and glycoproteins 350/220, 110, 85, 42, and 27). The glycoproteins of EBV are much less complex than those of HSV, and one in particular—gp350/220—is the main target of neutralizing antibodies and hence the principal focus of research attention.

Approaches for Vaccine Development. One approach that is being pursued is recombinant gp350, which does induce antibody-dependent cytotoxicity. In cotton-top tamarinds, this vaccine protects against lymphoma after a parenteral challenge. This approach would probably protect humans in pathologies that are dependent on replication, such as IM and nasopharyngeal carcinoma. In a very limited trial in China, 10 children were infected with gp350 in vaccinia and 10 got placebo; after a year, all 10 on placebo became infected with EBV,



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