The pneumovirus respiratory syncytial (RS) virus is the major viral cause of bronchiolitis and pneumonia in infants and children and no effective vaccine is available. Maternal antibody does not confer solid immunity on neonates and natural infection provides only partial protection against frequent repeat infections. To address this major public health problem, this research program has focused on the molecular biology of RS virus, characterizing the viral genes and gene products and examining the immune response to individual gene products. Until recently it has not been possible to address the relationship between the distinctive genomic regions and gene products of RS virus and the unusual pathogenesis of disease because it was not possible to engineer specific alterations into the genomes of these viruses and recover replicable, infectious RNA and virus. Recent technical advances have overcome this problem and opened the way to genetic analysis of every aspect of replication, both the unique cis-acting genetic elements and trans-acting protein factors in control of viral replication and in the pathogenesis of disease. The experiments in this proposal apply this technology to investigate previously inaccessible questions concerning the role of the unique RS virus gene products in the life cycle of the virus and in the progression of the virus to severe respiratory disease.
The specific aims are 1) To determine the mechanism of action of the RS virus M2 ORF1 protein as a transcription antiterminator; 2) To analyze the role of the M2 protein conserved Cys3His1 motif in transcription antitermination, N protein binding and binding of zinc; 3) To analyze the role of the M2 protein in the virus life cycle; 4) To investigate the role of the NS1 and NS2 proteins in infection; 5) To investigate the role of the glycoprotein G in the infection process; 6) To analyze the role of G and the secreted form of G in viral pathogenesis and spread; 7) To investigate the potential of gene rearrangement to alter the vral phenotype beneficially.
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