Although the infections caused by many mammalian viruses have been largely controlled in the developed world through a variety of vaccination strategies, there still remain many clinically devastating diseases caused by negative (-) strand RNA viruses, including measles, mumps, bronchiolitis (respiratory syncytial virus) and croup (parainfluenza viruses). Measles virus infection causes an acute respiratory syndrome and rash and in developed countries the patient usually recovers. However, in third world countries, measles infections produce much higher levels of morbidity and mortality. In rare cases a persistent, fatal infection of the central nervous system called subacute sclerosing panencephalitis (SSPE) can develop some 5-10 years following acute measles infection. In these cases highly mutated measles viruses termed SSPE viruses are the etiologic agent. SSPE is a striking example of a persistent virus infection of the brain and we believe that the analysis of the polymerase functions of wild type measles and SSPE viruses will lead to an understanding of persistence and ultimately of this unique disease process. We have developed systems with recombinant viral proteins to study measles virus RNA synthesis in vivo and it vitro. We propose to define the molecular mechanisms by which the measles virus RNA polymerase catalyzes the individual steps in transcription of the genome RNA. We will study the mechanism of transcription and P mRNA editing by identifying and characterizing the L and P gene defects in persistent and SSPE viruses that lead to altered RNA synthesis and RNA editing patterns. We propose to study the structure and function of the measles RNA polymerase complex, consisting of the viral L and P proteins. We will study the role of conserved domains I, II and VI of the measles L protein in transcription. Viral transcription is inhibited by the viral C protein and we will study the molecular basis for this regulation. Viral RNA synthesis appears to require host components and we will identify and characterize cellular proteins involved in transcription.
