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J. Virol. doi:10.1128/JVI.01439-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The Cytoplasmic Tail of the Human Respiratory Syncytial Virus F Protein Plays a Critical Role in Cellular Localization of the F Protein and Infectious Progeny Production

Department of Pathology, University of Virginia, Charlottesville, VA; University of Alabama Medical School, Birmingham, AL

^* To whom correspondence should be addressed. Email: gww4f{at}virginia.edu.

	Abstract

The importance of the F protein cytoplasmic tail (CT) for replication of human respiratory syncytial virus (HRSV) was examined by monitoring the behavior of viruses expressing F proteins with a modified COOH-terminus. The F protein mutant viruses were recovered and amplified under conditions where F protein function was complemented by expression of a heterologous viral envelope protein. The effect of the F protein modifications was then examined in the context of a viral infection in standard cell types (Vero and HEp-2). The F protein modifications consisted of a deletion of the predicted cytoplasmic tail (CT) or a replacement of the CT with the CT of the vesicular stomatitis virus (VSV) G protein. In addition, engineered HRSVs were examined that lacked all homologous glycoprotein genes (SH, G, and F) and expressed instead either the authentic VSV G protein or a VSV G containing the HRSV F protein CT. We found that deletion or replacement of the F protein CT seriously impaired the production of infectious progeny. Cells infected with viruses bearing CT modifications displayed increased F protein surface expression and increased syncytium formation. The distribution of F protein in the plasma membrane of infected cells was altered, resulting in an F protein that was evenly distributed rather than predominantly localized to virus-induced surface filaments. CT deletion or exchange also abrogated interaction of F protein with triton-insoluble lipid rafts. Addition of the F protein CT to the VSV G protein, expressed as the only viral glycoprotein in an HRSV genome, had the opposite effects: the number of infectious progeny was higher, surface distribution was changed from relatively even to localized, and the proportion of VSV G protein associated with lipid rafts was higher. Together, these results show that the HRSV F protein CT plays a critical role in F protein cellular localization and production of infectious virus, and suggest that the function provided by the CT is independent of the F protein ecto- and transmembrane domains and is mediated by F protein-lipid raft interaction.

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