Naturally Occurring Substitutions in the P/V Gene Convert the Noncytopathic Paramyxovirus Simian Virus 5 into a Virus That Induces Alpha/Beta Interferon Synthesis and Cell Death

Wansley, Elizabeth K.; Parks, Griffith D.

doi:10.1128/jvi.76.20.10109-10121.2002

Cited by 83 publications

(196 citation statements)

References 46 publications

(73 reference statements)

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“…However, there are other reports indicating that infection by RS virus does not induce apoptosis (11,50). It has been reported that mutant SV5 containing mutations in the shared N termini of V and P protein (known as CPIϪ virus) accelerates viral gene expression and causes increased cell death, with characteristics of apoptosis (60). Even though the mutant SV5 (CPIϪ virus) is different from rSV5V⌬C, they may induce cell death through similar pathways.…”

Section: Vol 78 2004 Paramyxovirus V Protein and Apoptosis 5075mentioning

confidence: 99%

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

Sun¹,

Rothermel²,

Shuman³

et al. 2004

J Virol

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The paramyxovirus family includes many well-known human and animal pathogens as well as emerging viruses such as Hendra virus and Nipah virus. The V protein of simian virus 5 (SV5), a prototype of the paramyxoviruses, contains a cysteine-rich C-terminal domain which is conserved among all paramyxovirus V proteins. The V protein can block both interferon (IFN) signaling by causing degradation of STAT1 and IFN production by blocking IRF-3 nuclear import. Previously, it was reported that recombinant SV5 lacking the C terminus of the V protein (rSV5V⌬C) induces a severe cytopathic effect (CPE) in tissue culture whereas wild-type (wt) SV5 infection does not induce CPE. In this study, the nature of the CPE and the mechanism of the induction of CPE were investigated. Through the use of DNA fragmentation, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling, and propidium iodide staining assays, it was shown that rSV5V⌬C induced apoptosis. Expression of wt V protein prevented apoptosis induced by rSV5V⌬C, suggesting that the V protein has an antiapoptotic function. Interestingly, rSV5V⌬C induced apoptosis in U3A cells (a STAT1-deficient cell line) and in the presence of neutralizing antibody against IFN, suggesting that the induction of apoptosis by rSV5V⌬C was independent of IFN and IFN-signaling pathways. Apoptosis induced by rSV5V⌬C was blocked by a general caspase inhibitor, Z-VAD-FMK, but not by specific inhibitors against caspases 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 13, suggesting that rSV5V⌬C-induced apoptosis can occur in a caspase 12-dependent manner. Endoplasmic reticulum stress can lead to activation of caspase 12; compared to the results seen with mock and wt SV5 infection, rSV5V⌬C infection induced ER stress, as demonstrated by increased expression levels of known ER stress indicators GRP 78, GRP 94, and GADD153. These data suggest that rSV5V⌬C can trigger cell death by inducing ER stress.

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Section: Vol 78 2004 Paramyxovirus V Protein and Apoptosis 5075mentioning

confidence: 99%

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

Sun¹,

Rothermel²,

Shuman³

et al. 2004

J Virol

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“…WT SV5 expressing green fluorescent protein (SV5-GFP) was recovered, as described previously (46), from a cDNA plasmid (16) kindly provided by Robert Lamb (Northwestern University) and Biao He (Penn State University). SV5-GFP stocks were grown in MDBK cells.…”

Section: Methodsmentioning

confidence: 99%

“…To construct the SV5 leader mutant Le-(U5C, A14G), PCR was used to introduce a T-to-C change in position 5 and an A-to-G change in position 14 of the leader region of the infectious clone for WT SV5-GFP. The Le-(U5C, A14G) mutant was recovered as described previously (46), with minor modifications.…”

Section: Methodsmentioning

confidence: 99%

“…Wild-type (WT) SV5 is a poor inducer of host cell responses, including the activation of proinflammatory cytokines and IFN-␤ (6,17,46). In contrast, we have shown previously that the naturally occurring SV5 variant Wake Forest isolate of parainfluenza virus (WF-PIV) has a delay in viral RNA synthesis but is a potent inducer of IL-8 and IFN-␤ responses (50).…”

mentioning

confidence: 99%

“…Sequence analysis has identified many nucleotide differences between WF-PIV and WT SV5 (50). Exchanging the P/V gene from WF-PIV or a second variant, CPI-, into an otherwise WT SV5 background results in a chimeric virus that overexpresses viral gene products and activates cytokine secretion and apoptosis (10,46,50). These results illustrate that chimeras can have phenotypes that are very different from those of the two parental viruses (10) and suggest that the trans-acting paramyxovirus gene products function in concert to coordinate viral gene expression and limit host cell responses.…”

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confidence: 99%

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Role for the Paramyxovirus Genomic Promoter in Limiting Host Cell Antiviral Responses and Cell Killing

Manuse

Parks

2009

J Virol

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Innate host cell responses to viral infection are important factors that play major roles in viral pathogenesis, adaptive immunity, and tropism for specific tissues or cells (2). These antiviral responses include the stimulation of type I interferon (IFN) pathways and the secretion of proinflammatory cytokines, such as interleukin-6 (IL-6) and 41). Paramyxoviruses, such as simian virus 5 (SV5), can prevent activation of host antiviral responses by directly inhibiting the pathways that lead to activation (4) or by attenuating the expression of viral products that are the activators of a host cell response (9). Here we provide evidence for the role of the viral genomic promoter in enabling SV5 to avoid activation of innate responses.Members of the paramyxovirus family of negative-strand RNA viruses employ a diverse range of mechanisms to circumvent host cell antiviral responses (reviewed in references 7 and 15). Many of these mechanisms for counteracting cytokine responses have been attributed to products of the paramyxovirus P/V (or P/V/C) gene, which, depending on the particular virus, encodes the phosphoprotein P subunit of the RNAdependent RNA polymerase, the accessory V protein, and in some cases the family of C proteins (8,26,14,33). For SV5, accurate transcription of the P/V gene results in an mRNA coding for the V protein. The P mRNA is identical to the V mRNA except for the addition of two nontemplated G residues that are inserted by the viral polymerase at a precise location in the P/V transcript (44). The P and V proteins have unique C-terminal regions, with the V protein encoding a highly conserved cysteine-rich domain that is required for many V-associated functions (8,17,38).A major function of the SV5 V protein is the inhibition of IFN signaling, which occurs through V-mediated targeting of signal transducer and activator of transcription 1 (STAT1) for ubiquitylation and degradation (1,8,45). The SV5 V protein also blocks activation of the IFN-␤ promoter during virus infection (17) or following transfection of double-stranded RNA (dsRNA) (4, 38). The paramyxovirus V protein inhibits IFN-␤ induction by targeting the IFN-inducible RNA helicase encoded by the melanoma differentiation-associated gene 5 (mda-5) (4, 5). Inhibition of mda-5 activation requires only the V protein cysteine-rich C-terminal domain (4, 38), which prevents mda-5 from binding dsRNA and self-association (5). In contrast, the alternative RNA helicase retinoic acid-inducible gene I (RIG-I) does not appear to be inhibited by V protein (4, 5). V protein also appears to act as a decoy substrate for kinases that activate IFN regulatory factor 3 (IRF-3) (29) and . Similarly, the SV5 V protein is reported to block IL-6 induction (27), although virus-infected cells still respond to tumor necrosis factor alpha-mediated induction of .In addition to the V protein, some paramyxoviruses, such as Sendai virus (SeV) and measles virus, encode a group of C proteins that are expressed from the P/V/C gene (26). The SeV

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Respiroviruses: Parainfluenza Virus

Peluso¹,

Moscona²

2010

Topley &Amp; Wilson's Microbiology and Microbial Infections

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Naturally Occurring Substitutions in the P/V Gene Convert the Noncytopathic Paramyxovirus Simian Virus 5 into a Virus That Induces Alpha/Beta Interferon Synthesis and Cell Death

Cited by 83 publications

References 46 publications

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

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

Role for the Paramyxovirus Genomic Promoter in Limiting Host Cell Antiviral Responses and Cell Killing

Respiroviruses: Parainfluenza Virus

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