Mechanism of Respiratory Syncytial Virus Fusion

Research Inst Nationwide Children'S Hosp, Columbus OH

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Abstract

Respiratory syncytial virus (RSV) infection remains an important medical problem for infants and the elderly. Infection requires the fusion of the viral membrane with the target cell membrane, which delivers the viral genome to the target cell cytoplasm. The viral fusion (F) protein, one of the three viral glycoproteins, performs this function. It is clear from the crystal structures of two related viruses, one in the pre-triggered and one in the post-triggered form, that the F protein undergoes massive changes in structure to accomplish membrane fusion. Based on these structures, models of the pre-triggered and post-triggered RSV F protein have been generated. Using the pre-triggered model, the most likely sites for attachment to target cells and/or for triggering have been identified. Mutation of the amino acids in these sites to alanine will test their importance in cell-cell fusion. Mutations that prevent fusion without preventing the F protein from reaching the cell surface will be studied further in a soluble version of the RSV F protein, sF. The sF protein in its pre-triggered form has been produced for the first time, enabling the determination of whether a mutation that blocks fusion inhibits attachment, triggering, or protein movements. Movements of the F protein will be further studied by the introduction of intermonomer disulfide bonds to trap the F protein. Overall, these studies will result in the identification of functional domains in the F protein that can be used to rapidly screen for novel antiviral compounds and to develop novel vaccines.