Gamma herpesviruses are associated with animal and human tumors of both immunocompromised and otherwise normal individuals. Like many DNA viruses, these viruses encode homologues of cellular proteins that differ in significant ways from their cellular counterparts. The retention of some functions, gain of new functions and loss of other functions by these viral versions apparently results in specific advantages to the virus. Individual gamma herpesviruses encode one or more open reading frames with recognizable homology to such cellular factors as chemokines, interleukins, interleukin receptors, cyclin, FLIP and BCL-2. Common to all gamma herpesviruses sequenced to date is a viral homologue of cellular BCL-2. The human Bcl-2 gene was first identified at the characteristic translocation breakpoints in follicular lymphoma leading to overexpression of BCL-2 protein. Shortly thereafter, BCL-2 was shown to function as an unusual oncogene by inhibiting cell death without stimulating cell proliferation. The role of viral BCL-2 homologues in viral replication and pathogenesis are yet unclear. In addition, the function of cellular BCL-2 is not fully understood and these pared down viral versions of cellular BCL-2 are likely to reveal important clues about their functions. We seek to characterize the functions of the BCL-2 homologues encoded by Kaposi's sarcoma herpesvirus (KSBcI-2) and Epstein-Barr virus (BHRF1 and BALF1).
In Aim 1, we will study the function of BHRF1/KSBcI-2 in membranes and compare its ability to form pores, translocate molecules of different sizes and regulate mitochondrial function compared to cellular BCL-2 family proteins. These results are expected to help separate the protective functions of BCL-2 family proteins from their killing function and other potential functions.
In Aim 2, we will explore the molecular mechanisms by which BALF1 inhibits the anti-apoptotic function of BF-IRF1.
In Aim 3, the expression patterns of BHRF1 and BALF1 during virus infections will be explored by inserting tags into the their reading frames within the Epstein-Barr virus genome.