Bovine Respiratory Syncytial Virus Nonstructural Proteins NS1 and NS2 Cooperatively Antagonize Alpha/Beta Interferon-Induced Antiviral Response

Abstract

Bovine respiratory syncytial virus (BRSV) is a major etiological agent of respiratory tract disease in calves and results in substantial economic loss (40,45). The immune response and pathology in calves mimic symptoms caused by human respiratory syncytial virus (HRSV), which remains the leading cause of serious bronchiolitis and pneumonia in infants and young children throughout the world (9). Molecular cloning has confirmed a very close relationship between BRSV and HRSV and has revealed substantial differences from other members of the Paramyxoviridae family, leading to the establishment of the Pneumovirus genus within the Paramyxoviridae family (36, 37).As with all members of the order Mononegavirales, the 15-kb genomic RNA of RSV is contained in a ribonucleoprotein (RNP) complex which serves as a template for sequential transcription of genes (25, 49). Eleven proteins are expressed from 10 transcription units, which are arranged in the order 3Ј-NS1-NS2-N-P-M-SH-G-F-M2-L-5Ј (5, 9, 30, 31). The proteins encoded include five RNP-associated proteins, namely, the nucleoprotein N, the phosphoprotein P, the large catalytic subunit L of the RNA polymerase, and a transcription elongation factor (M2-1) encoded by the first of two overlapping open reading frames of the M2 gene (8,17,27,38). The second open reading frame of the M2 transcription unit (M2-2) was reported to encode a nonessential protein (1) which is probably involved in the regulation of RNA synthesis (4, 28). Three viral proteins are associated with the viral envelope, namely, the fusion protein F, the putative attachment protein G, and a small hydrophobic protein SH.The presence of two nonstructural protein genes, NS1 and NS2, at the 3Ј-terminal position of the genome distinguishes pneumoviruses from all other members of the Mononegavirales. Due to the 3Ј-proximal location, the NS genes are abundantly transcribed. The encoded proteins have been demonstrated in infected cells (10,16). The BRSV NS1 and NS2 genes encode polypeptides of 136 and 124 amino acids, respectively. Comparison with NS proteins of HRSV subgroup A and B proteins revealed amino acid identities of 69 and 68% for NS1 proteins and 84 and 83%, for NS2 proteins, respectively (5, 34). The deduced sequences, however, did not provide obvious clues to the function of NS proteins in the virus life cycle. The HRSV NS1 protein was reported to be associated with the M protein, while the NS2 protein did not show any detectable association with RSV structural proteins, indicating distinct functions of NS1 and NS2 (16,47). An inhibitory function of NS1 in virus RNA transcription and RNP replication was recently suggested by experiments in which artificial HRSV minigenomes were grown in the absence or presence of NS1. In the same study, an inhibitory but far less pronounced effect was also observed for NS2 (3).Recently established protocols for recovery of infectious minus-strand RNA viruses from cDNA (11) have allowed the generation of recombinant HRSV (8, 29) and BRSV (5) and allowed researchers to...

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