Epstein-Barr virus (EBV) infects most humans and causes infectious mononucleosis. In some immune suppressed humans, such organ transplant recipients, children with generic susceptibility or AIDS patients, EBV causes an acute malignant lymphoproliferative disease. EBV can predispose an infected cell to evolve into a Burkitt lymphoma or a nasopharyngeal carcinoma. EBV efficiently transforms normal B lymphocytes so they can proliferate indefinitely, in vitro, in SCID mice or in tarmarins. The goal of this research program is to delineate the biochemical processes by which EBV infects and alters human B lymphocyte growth. In transformed human B lymphocytes EBV expresses six nuclear proteins (EBNA-1, -2,-3A, -3B, -3C and-LP), two integral membrane proteins (LMP-1 and LMP-2) and two small RNAs (EBERS). The genes and gen products are characterized. Relevant biochemical effects of these genes in B lymphocytes are also known. Initial data from recombinant EBV molecular genetic analyses indicates that EBNA-2, -LP, -3A, -3C and LMP-1 are critical for lymphocyte growth transformation; and that EBNA-3B LMP-2 and the EBERs are not. (EBNA-1 has not been evaluated. The objectives of this proposal are (i) to continue the delineation of the biochemical pathways by which these genes effect lymphocyte growth. (ii) to exploit recently developed recombinant EBV molecular genetics to define domains of these genes of the encoded proteins which are critical for EBV effects on lymphocyte growth. (iii) to couple the genetic and biochemical analyses so as more rapidly delineate essential interactions. (iv) to characterize B lymphocyte genes whose expression is altered by EBV infection and to place these genes in the pathways of EBV and antigen effects. Collaborative interactions to further characterize relevant aspects of human EBV infection and of the immune response will continue. These experiments may identify pharmacologic targets for inhibiting EBV infection and contribute to the development of EBV vaccines and vectors. Since the effects of EBV on B lymphocytes closely parallel those of antigen stimulation, these studies are expected to increasingly intersect with and contribute to pathways of antigen driven B lymphocyte proliferation.
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