Newcastle Disease Virus V Protein Is a Determinant of Host Range Restriction

Abstract

). We now show that the NDV V protein plays an important role in host range restriction. In order to study V functions in vivo, recombinant NDV (rNDV) mutants, defective in the expression of the V protein, were generated. These rNDV mutants grow poorly in both embryonated chicken eggs and chicken embryo fibroblasts (CEFs) compared to the wild-type (wt) rNDV. However, insertion of the NS1 gene of influenza virus A/PR8/34 into the NDV V(؊) genome [rNDV V(؊)/NS1] restores impaired growth to wt levels in embryonated chicken eggs and CEFs. These data indicate that for viruses infecting avian cells, the NDV V protein and the influenza NS1 protein are functionally interchangeable, even though there are no sequence similarities between the two proteins. Interestingly, in human cells, the titer of wt rNDV is 10 times lower than that of rNDV V(؊)/NS1. Correspondingly, the level of IFN secreted by human cells infected with wt rNDV is much higher than that secreted by cells infected with the NS1-expressing rNDV. This suggests that the IFN antagonist activity of the NDV V protein is species specific. Finally, the NDV V protein plays an important role in preventing apoptosis in a species-specific manner. The rNDV defective in V induces apoptotic cell death more rapidly in CEFs than does wt rNDV. Taken together, these data suggest that the host range of NDV is limited by the ability of its V protein to efficiently prevent innate host defenses, such as the IFN response and apoptosis.Newcastle disease virus (NDV), an avian paramyxovirus, is classified as the only member of the genus Avulavirus belonging to the family Paramyxoviridae within the order Mononegavirales (http://www.ictvdb.iacr.ac.uk/Ictv/fr-fst-a.htm). NDV is an economically important pathogen, since periodic outbreaks affect the poultry industry. NDV is also considered a potential oncolytic agent in the treatment of cancer because it can selectively kill tumor cells (29). NDV isolates are categorized as velogenic (highly virulent), mesogenic (intermediate), or lentogenic (nonvirulent), depending on the severity of the disease they cause (2). A critical molecular determinant for the pathogenicity of NDV appears to be the cleavage site of the fusion (F) protein (20).The NDV genome is 15,186 nucleotides long, and it consists of six transcriptional units that encode the nucleocapsid protein (NP), phosphoprotein (P), matrix protein (M), F protein, hemagglutinin protein (HN), and the polymerase protein (L). Two additional proteins, V and W, are expressed by mRNAs, which are derived from the P gene via RNA editing (26,30,31). These V and W proteins share their amino (N)-terminal domains with the P protein and vary at their carboxy (C) termini. The NDV V protein, similar to other paramyxovirus V proteins, has a cysteine-rich C-terminal domain which binds two atoms of Zn 2ϩ (30). It has been demonstrated that plasmid-mediated expression of the NDV V protein or of its C-terminal domain inhibits the alpha/beta interferon (IFN-␣/␤) response (19). We now show, using reverse gene...

Newcastle disease virus, a host range-restricted virus, as a vaccine vector for intranasal immunization against emerging pathogens

“…Differences between avian and primate cells with regard to sialic acid receptors for viral attachment comprise one possible factor in the host range restriction. It also might be that NDV is less able to block the type I IFN response in primate cells, as suggested by previous studies (40). In the case of the host range restriction of bovine parainfluenza virus type 3 in primates, each gene appeared to make a contribution (41).…”

Conserved Cysteine-Rich Domain of Paramyxovirus Simian Virus 5 V Protein Plays an Important Role in Blocking Apoptosis

“…The phenotype of rSeV⌬V is very similar to that of rSV5V⌬C (i.e., increased CPE in culture and attenuated in vivo), suggesting that SeV V protein might have a function similar to that of SV5 V protein in preventing cell death. Recently, a recombinant NDV lacking its V gene (rNDV⌬V) has been recovered that induces increased apoptosis in CEF cells, suggesting that NDV V has an anti-apoptosis function (38). The mechanism by which V protein blocks virus-induced apoptosis is not clear.…”

Selective oncolytic effect of an attenuated Newcastle disease virus (NDV-HUJ) in lung tumors

“…17 NDV, an avian virus, may represent a different example of oncolytic virus as its V gene product, that is known to counteract IFN response in avian cells, is completely inactive in mammalian cells. 39 Notwithstanding, the oncolytic effect of NDV was shown related to a deficient IFN system in one study 15 and conversely shown independent of the IFN system in yet another study. 19 To further investigate the role of the IFN system in the oncolytic mechanism of NDV-HUJ, we pretreated the cells with recombinant IFN-b and tested for replication and the oncolytic activities of the virus.…”