This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Arenaviruses merit significant interest both as tractable experimental model systems to study acute and persistent viral infections and as clinically important human pathogens. Several arenaviruses, chiefly Lassa virus (LASV) cause hemorrhagic fever (HF) disease in humans, whereas the prototypic Arenavirus LCMV is a superb workhorse for the investigation of basic concepts in the fields of viral immunology and pathogenesis. In addition, evidence indicates that LCMV is a neglected human pathogen of clinical significance. Our long-term objective is to obtain a detailed understanding of the Arenavirus molecular and cell biology. This knowledge will contribute to the elucidation of Arenavirus-host interactions and associated diseases, and facilitate the development of effective strategies to combat arenaviral infections for which there are not licensed vaccines and current therapy is limited to the use of ribavirin, which is only partially effective and often associated with severe side effects. We have identified the arenavirus Z protein as the driving force of virus budding, and shown that LASV Z budding activity is mediated by the presence of bona fide late (L) domains PPPY and PTAP in Z. Many enveloped viruses are capable, via L domains present in their budding proteins, to interact with and hijack the cellular multivesicular body (MVB) machinery to escape the cell. The focus of this proposal is to identify and functionally characterize host proteins that influence Z-mediated budding.
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