The M2-2 protein of human respiratory syncytial virus is a regulatory factor involved in the balance between RNA replication and transcription

Citation
A. Bermingham et Pl. Collins, The M2-2 protein of human respiratory syncytial virus is a regulatory factor involved in the balance between RNA replication and transcription, P NAS US, 96(20), 1999, pp. 11259-11264
Citations number
29
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN journal
00278424 → ACNP
Volume
96
Issue
20
Year of publication
1999
Pages
11259 - 11264
Database
ISI
SICI code
0027-8424(19990928)96:20<11259:TMPOHR>2.0.ZU;2-1
Abstract
The M2 mRNA of human respiratory syncytial virus (RSV) contains two overlap ping ORFs, encoding the transcription antitermination protein (M2-1) and th e 90-aa M2-2 protein of unknown function. Viable recombinant RSV was recove red in which expression of M2-2 was ablated, identifying it as an accessory factor dispensable for growth in vitro. Virus lacking M2-2 grew less effic iently than did the wild-type parent in vitro, with titers that were reduce d 1,000-fold during the initial 2-5 days and 10-fold by days 7-8. Compared with wild-type virus, the intracellular accumulation of RNA by M2-2 knockou t virus was reduced 3- to 4-fold or more for genomic RNA and increased 2- t o 4-fold or more for mRNA, Synthesis of the F and G glycoproteins, the majo r RSV neutralization and protective antigens, was increased in proportion w ith that of mRNA. In cells infected with wild-type RSV, mRNA accumulation i ncreased dramatically up to ap proximately 12-15 hr after infection and the n leveled off, whereas accumulation continued to increase in cells infected with the M2-2 knockout viruses. These findings suggest that M2-2 mediates a regulatory "switch" from transcription to RNA replication, one that provi des an initial high level of mRNA synthesis followed by a shift in the RNA synthetic program in favor of genomic RNA for virion assembly. With regard to vaccine development, the M2-2 knockout has a highly desirable phenotype in which virus growth is attenuated while gene expression is concomitantly increased.