The long term objective is to understand the molecular basis of cytomegalovirus (CMV) replication and use that information to develop new ways to diagnose and treat CMV-related diseases of man. This will be accomplished by identifying and studying the synthesis, structure, and function of specific viral proteins that are essential for virus replication. In this application for renewed support (20th year) there are five specific aims intended to provide a better understanding of the assembly and structure of the CMV virion and its precursors. The rationale for studying virus structure and assembly is that most aspects of virus replication are directly or indirectly coupled to the assembly process; therefore, it ultimately represents a major and largely untapped source of new targets for antivirals. CMV has been selected as a model system because of its increasing medical relevance in association with AIDS, organ transplantation, sexually transmitted disease and birth defects; and because of the need to determine molecular similarities and differences between herpes group viruses in order to understand their biological differences. In this proposal, a major research emphasis is placed on a """"""""scaffolding""""""""-like protein, called the assembly protein precursor, which together with its genetically related proteinase, is intimately involved in the process of capsid formation and possibly DNA packaging. Experiments are outlined to determine the function of five newly discovered domains on this protein: two are nuclear localization signals, two mediate protein-protein interactions in the capsid, and one is a CKII-like phosphorylation site. A second major research focus will be on the protein product of the largest open reading frame in the viral genome. This protein is a virion tegument constituent and forms a high molecular weight complex with a 115-kDa protein in both cells and virions. Genetic, biochemical, and immunologic techniques will be used to determine the structure and function of these proteins and the complex that they form.
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