After the human respiratory syncytial virus A (hRSV A) enters host cells, an initial round of transcription and translation of virally-encoded mRNAs ensues, which is followed by genome replication.

The negative sense, single-stranded RNA (-ssRNA) genome of the human respiratory syncytial virus (RSV) A is 15.2 kb long and contains 10 genes that encode 11 proteins. The 10 genes, going from the 3' end to the 5' end of the -ssRNA are: 1C (NS1), 1B (NS2), N, P, M, SH, G, F, M2, and L. Except for the M2 gene, each gene encodes one protein. The two overlapping open reading frames (ORFs) of the M2 gene encode proteins M2-1 and M2-2.

The N gene encodes the nucleoprotein, which forms decameric and hendecameric (11-fold) rings around which viral genomic RNA is packaged. The L and P genes encode the large polymerase subunit and the phosphoprotein polymerase cofactor subunit, respectively, of the RNA-dependent RNA polymerase complex (RdRP) (reviewed in Battles and McLellan 2019). The L protein contains three conserved enzymatic domains: the RNA-dependent RNA polymerase (RdRp) domain, the polyribonucleotidyl transferase (PRNTase or capping) domain, and the methyltransferase (MTase) domain (reviewed in Sutto-Ortiz et al. 2023). The M2-1 product of the M2 gene is a transcription processivity factor, while the M2-2 product of the M2 gene is a nonstructural protein that regulates the switch between transcription and genome replication. The SH, G, and F genes encode three proteins that are embedded in the viral envelope: small hydrophobic protein, attachment protein, and fusion protein, respectively. The secreted isoform of G protein (sG) mediates immune evasion. The NS1 and NS2 genes encode nonstructural proteins that function together to inhibit apoptosis and interferon response in infected cells. For review, please refer to Battles and McLellan 2019.

The genomic -ssRNA and the antigenome RNA are encapsidated as they are synthesized, and the association of the nascent RNA with the N protein is likely what causes the replicating polymerase to be processive, with the processivity being further augmented by the M2-1 processivity factor (reviewed in Fearns and Deval 2016). The C-terminal arm of the N protein, known to interact with the P protein subunit of RdRP complex, extends above the plane of N decamers. The interaction between N and P proteins may allow the RdRP complex to distort the helical conformation of the nucleocapsid during RNA synthesis. A long beta-hairpin in the N-terminal region of the N protein may be the site of contact with the catalytic L subunit of the RdRP complex. The proposed model for RNA synthesis in RSV is that the RdRP complex induces a hinge movement of the N-terminal region with respect to the C-terminal region of the N protein that allows the polymerase to thread through the template RNA without the need to disassemble the nucleocapsid (Tawar et al. 2009). The hinge movement would enable 11 bases available for readout at a time (Tawar et al. 2009), consistent with the accumulation of abortive transcripts 9-11 nucleotides in length in P protein phosphorylation mutants that impair transcript elongation (Dupuy et al. 1999).

The M2-2 protein regulates the shift from positive to negative sense RNA synthesis. While the mechanism has not been fully elucidated, M2-2 was shown to directly bind to the L protein and to inhibit positive sense RNA synthesis (reviewed in Noton and Fearns 2015).

For review, please refer to Collins et al. 2013.