Respiratory syncytial virus (RSV) infections of the airways are the most frequent cause of hospitalization for infants. They are also a cause of death for the elderly, nearly as important as influenza in non-epidemic years. We are working to understand how RSV attacks cells in the airways. We have found that laboratory-adapted strains of RSV use a different mechanism to enter cultured cells than do RSV strains directly from patients, but we have also discovered a cell line that allows us to grow RSV directly from patients without causing this laboratory adaptation. This virus enables us, for the first time, to search for the RSV receptor on the cells lining the airways.

The second step in virus entry is fusion of the virus membrane with the target cell membrane, spilling the virus genome into the cell to initiate infection.  We are working to identify the trigger point in the RSV F protein that initiates fusion.  Recent publication of the pre- and post-fusion structures of the F protein from similar viruses has enabled us to model the RSV F protein and led to novel ideas on how it is triggered.  Once we understand the way the F protein is triggered, we will be able to design drugs to trigger it before the virus is in contact with a target cell, thereby inactivating it.

We have found that RSV only infects airway cells that have hair-like projections called cilia on their surface. In cystic fibrosis patients, because these “ciliated” cells are missing the CFTR channel they are unable to maintain the proper water balance in the mucus coating over them. The result is that the mucus that covers the airways becomes very thick. Since RSV naturally infects these ciliated cells, we are attempting to use RSV as a gene therapy vector to treat children with cystic fibrosis. So far, we have been able to make an altered form of RSV that does not kill cells, to express the CFTR channel from it, and to “mobilize” the replicon into virus particles ready for delivery to target cells.