Viruses are parasites of their hosts. Hence, the life cycle of any virus is inextricably tied to that of the host cell. Despite this dependence, all viruses share a number of essential tasks which they must accomplish for survival. A virus must be able to find and recognize a cell in which it can replicate, release its genome into the cell, generate new viral components by transcription and translation and assembly these components into precursors that mature into a stable progeny virion which is released from the host cell and transmitted to encounter a new host. Different viruses accomplish these tasks in different ways as a result of adaptation to different cellular environments. Each of these tasks involves interactions between components within the context of the whole virion and hence require the visualization of the entire structure at which the techniques of cryo-transmission electron microscopy (cryoTEM) and three-dimensional (3D) image reconstruction ('cryo-reconstruction') excel. We have exploited cryo-reconstruction techniques to study a diverse range of viruses, including those that infect mammals as well as insects, bacteria, and plants (including fungi and algae). Several studies funded by the current PPG have illustrated the structural response of different viruses to the common tasks of the viral life cycle. This proposal involves several new cryo-reconstruction studies aimed at exploring the structural basis for key aspects of viral infection. Work with the Kuhn and Rossmann laboratories will continue analyses of the assembly of several enveloped viruses of the alphavirus gene (Togavirus family). We will also initiate new studies of the assembly of three important human pathogenesis: rubella virus (rubrivirus genus) and two members of the closely related Flavivirus family of enveloped viruses, yellow fever virus and Hepatitis C virus. A collaboration with Smith's laboratory will address issues related to viral transmission in two plant viruses, cucumber mosaic virus and zucchini yellow mosaic virus. A collaboration with Friedman's laboratory will define viral epitopes on human papilloma viruses, including the carcinogenic, HPV serotype 16.
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