DESCRIPTION: Viruses have the ability to shape the history and evolution of their hosts. Since most organisms can be infected by viruses, it is of great importance to study how viruses interact with their hosts. On the cellular level, viral proteins often interact with and manipulate host cellular proteins, to create favorable conditions for viral replication and survival. To study the interactions between Epstein-Barr virus proteins and cellular proteins, we have developed a Drosophila model of early Epstein-Barr viral infection. Epstein-Barr virus encodes two immediate early genes, BZLF1 and BRLF1, both of which physically and functionally interact with several different host proteins. We have created transgenic fly lines that express the BZLF1 gene in specific tissues. To understand how the BZLF1 protein interacts with cellular proteins, we performed a genetic screen by mutating wild-type males and crossing these males to one of our transgenic BZLF1 lines, GMR::Z. We isolated several modifier genes, each of which enhanced BZLF1 activity. One of the modifiers has been identified as a homolog of the human Pax5 gene. We now will characterize the remaining modifiers, in order to identify which Drosophila genes, as well as human homologs, they correspond to. In Specific Aim 1, we will pin-point the locations of the modifier genes to identify the specific genes they correspond to. To do this, we will create more alleles of two modifier genes (this will make mapping easier) by mutagenizing male flies and crossing these to females of the modifier stocks. We will examine their progeny for non-complementation (in the form of lethality). To map each modifier stock, we will use standard meiotic mapping techniques with stocks available from the Bloomington stock center. Since the entire Drosophila genome has been sequenced, we will be able to determine which fly genes correspond to our modifier lines, once they have been mapped to specific locations. In Specific Aim 2, we will determine if there are human homologs to our Drosophila modifier genes. We will then obtain clones of the human genes and look for physical and functional interactions between the products of these genes and BZLF1. These studies will allow us to determine the importance of the initial genetic interactions we found in our modifier screen, in terms of EBV biology and pathogenesis. Epstein-Barr virus infects approximately 95% of the world's human population and is responsible for infectious mononucleosis, as well as a number of cancers. Since Epstein-Barr virus associated cancers such as nasopharyngeal carcinoma are found in specific populations, there may be a genetic link to Epstein-Barr virus-mediated cancer formation. Our studies aim to find human genes whose protein products enhance or suppress Epstein-Barr virus protein activity. [unreadable] [unreadable] [unreadable]