Abstract:
:Foot-and-mouth disease (FMD), which is caused by FMD virus (FMDV), remains a major plague among cloven-hoofed animals worldwide, and its outbreak often has disastrous socioeconomic consequences. A live-attenuated FMDV vaccine will greatly facilitate the global control and eradication of FMD, but a safe and effective attenuated FMDV vaccine has not yet been successfully developed. Here, we found that the internal ribosome entry site (IRES) element in the viral genome is a critical virulence determinant of FMDV, and a nucleotide substitution of cytosine (C) for guanine (G) at position 351 of the IRES endows FMDV with temperature-sensitive and attenuation (ts&att) phenotypes. Furthermore, we demonstrated that the C351G mutation of IRES causes a temperature-dependent translation defect by impairing its binding to cellular pyrimidine tract-binding protein (PTB), resulting in the ts&att phenotypes of FMDV. Natural hosts inoculated with viruses carrying the IRES C351G mutation showed no clinical signs, viremia, virus excretion, or viral transmission but still produced a potent neutralizing antibody response that provided complete protection. Importantly, the IRES C351G mutation is a universal determinant of the ts&att phenotypes of different FMDV strains, and the C351G mutant was incapable of reversion to virulence during in vitro and in vivo passages. Collectively, our findings suggested that manipulation of the IRES, especially its C351G mutation, may serve as a feasible strategy to develop live-attenuated FMDV vaccines.IMPORTANCE The World Organization for Animal Health has called for global control and eradication of foot-and-mouth disease (FMD), the most economically and socially devastating disease affecting animal husbandry worldwide. Live-attenuated vaccines are considered the most effective strategy for prevention, control, and eradication of infectious diseases due to their capacity to induce potent and long-lasting protective immunity. However, efforts to develop FMD virus (FMDV) live-attenuated vaccines have achieved only limited success. Here, by structure-function study of the FMDV internal ribosome entry site (IRES), we find that the C351 mutation of the IRES confers FMDV with an ideal temperature-sensitive attenuation phenotype by decreasing its interaction with cellular pyrimidine tract-binding protein (PTB) to cause IRES-mediated temperature-dependent translation defects. The temperature-sensitive attenuated strains generated by manipulation of the IRES address the challenges of FMDV attenuation differences among various livestock species and immunogenicity maintenance encountered previously, and this strategy can be applied to other viruses with an IRES to rationally design and develop live-attenuated vaccines.
journal_name
J Viroljournal_title
Journal of virologyauthors
Yang D,Sun C,Gao R,Wang H,Liu W,Yu K,Zhou G,Zhao B,Yu Ldoi
10.1128/JVI.00990-20subject
Has Abstractpub_date
2020-07-30 00:00:00issue
16eissn
0022-538Xissn
1098-5514pii
JVI.00990-20journal_volume
94pub_type
杂志文章abstract::Hepatitis E virus (HEV) is a common cause of acute viral hepatitis worldwide. Most HEV infections are asymptomatic, but immunocompromised patients infected with HEV genotype 3 (HEV3), HEV4, or HEV7 may develop chronic infections. The HEV particles in stools are naked (nHEV), while those in the serum and culture supern...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01207-18
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.77.14.7903-7913.2003
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abstract::Infection with human papillomavirus (HPV) is a critical factor in the pathogenesis of most cervical cancers and some aerodigestive cancers. The HPV E6 oncoprotein from high-risk HPV types contributes to the immortalization and transformation of cells by multiple mechanisms, including degradation of p53, transcriptiona...
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pub_type: 杂志文章
doi:10.1128/JVI.01942-05
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abstract:UNLABELLED:Kaposi's sarcoma-associated herpesvirus (KSHV) typically displays two different phases in its life cycle, the default latent phase and the lytic phase. There is a short period of lytic gene expression in the early stage of KSHV primary infection. The factors involved in the shutdown process of lytic gene exp...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00596-14
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abstract::Normal levels of the hypermodified pyrimidine, alpha-putrescinylthymine, which is formed from hydhydroxymethyluracil at the polynucleotide level (Maltman et al., J. Virol. 34:354-359, 1984), are not required in bacteriophage luminal diameterW-14 DNA for the DNA to serve as a replicative template in luminal diameterW-1...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.52.3.1036-1038.1984
更新日期:1984-12-01 00:00:00
abstract::A covalently closed circular form of unintegrated viral DNA obtained from NIH 3T3 cells freshly infected with Moloney murine leukemia virus (M-MLV) and a port of the endogenous M-MLV from the BALB/Mo mouse strain have been cloned in bacteriophage lambda. The unintegrated viral DNA was cleaved with restriction endonucl...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.36.1.254-263.1980
更新日期:1980-10-01 00:00:00
abstract::Many viruses express inhibitors of programmed cell death (apoptosis), thereby countering host defenses that would otherwise rapidly clear infected cells. To counter this, viruses such as adenoviruses and herpesviruses express recognizable homologs of the mammalian prosurvival protein Bcl-2. In contrast, the majority o...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01115-12
更新日期:2012-11-01 00:00:00
abstract::The hepadnavirus reverse transcriptase is a multifunction enzyme. In addition to its role in DNA synthesis, the polymerase is required for RNA packaging and also functions as the primer for minus-strand DNA synthesis. Previously, we demonstrated that the protein-priming activity of the polymerase requires a viral RNA ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.12.8437-8442.1994
更新日期:1994-12-01 00:00:00
abstract::The monoclonal antibody PAb280 binds to small t antigen but not to large T antigen. Its binding site within the unique region of small t antigen was localized by studying its reaction with simian virus 40 mutants, other papovaviruses, and bacterial expression vectors coding for fragments of small t antigen. The antibo...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.63.7.3128-3134.1989
更新日期:1989-07-01 00:00:00
abstract::The human immunodeficiency virus type 1 (HIV-1) Tat protein is essential for viral replication and stimulates transcription of the integrated provirus by recruiting the kinase complex TAK/P-TEFb, composed of cyclin T1 (CycT1) and Cdk9, to the viral TAR RNA element. TAK/P-TEFb phosphorylates the RNA polymerase II compl...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.21.10579-10587.2002
更新日期:2002-11-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.80.5.2437-2444.2006
更新日期:2006-03-01 00:00:00
abstract::DNA sequence analysis has revealed that the gene coding for the human cytomegalovirus (HCMV) DNA polymerase is present within the long unique region of the virus genome. Identification is based on extensive amino acid homology between the predicted HCMV open reading frame HFLF2 and the DNA polymerase of herpes simplex...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.61.1.125-133.1987
更新日期:1987-01-01 00:00:00
abstract::Influenza A viruses (IAVs) remain a significant public health threat, causing more than 300,000 hospitalizations in the United States during the 2015-2016 season alone. While only a few IAVs of avian origin have been associated with human infections, the ability of these viruses to cause zoonotic infections further in...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02011-18
更新日期:2019-03-05 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00552-14
更新日期:2014-09-01 00:00:00
abstract::Highly pathogenic influenza A viruses (IAV) from avian hosts were first reported to directly infect humans 20 years ago. However, such infections are rare events, and our understanding of factors promoting or restricting zoonotic transmission is still limited. One accessory protein of IAV, PB1-F2, was associated with ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00425-18
更新日期:2018-05-14 00:00:00
abstract::Infection of Escherichia coli with the satellite virus P4 without its helper bacteriophage P2 leads either to the immune integrated state or to the nonimmune multicopy plasmid condition. We analyzed the transcription pattern of the phage plasmid P4 early and late after infection and during the stable plasmid or lysoge...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.62.5.1697-1704.1988
更新日期:1988-05-01 00:00:00
abstract::Rabies virus (RV) vaccine strain-based vectors show significant promise as potential live-attenuated vaccines against human immunodeficiency virus type 1 (HIV-1). Here we describe a new RV construct that will also likely have applications as a live-attenuated or killed-particle immunogen. We have created a RV containi...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.77.23.12782-12794.2003
更新日期:2003-12-01 00:00:00
abstract::Five urea-resistant and two heat-resistant mutants of poliovirus types 1 and 2 were isolated and their structural and nonstructural polypeptides compared to those of their wild-type, parental strains in an attempt to correlate mutant phenotypes with alterations in specific capsid polypeptides. Four of the seven mutant...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.14.4.821-833.1974
更新日期:1974-10-01 00:00:00
abstract::Protein P4, an early protein of double-stranded RNA bacteriophage phi 6, is a component of the virion-associated RNA polymerase complex and possesses a nucleoside triphosphate (NTP) phosphohydrolase activity. We have produced and characterized a panel of 20 P4-specific monoclonal antibodies. Epitope mapping using trun...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.67.5.2879-2886.1993
更新日期:1993-05-01 00:00:00
abstract::Due to the biological significance of the carbohydrate component of the human immunodeficiency virus type 1 (HIV-1) glycoproteins in viral pathogenesis, the glycosylation step constitutes an attractive target for anti-HIV therapy. Cyanovirin N (CV-N), which specifically targets the high-mannose (HM) glycans on gp120, ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.12.7777-7784.2005
更新日期:2005-06-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.15.7179-7186.2000
更新日期:2000-08-01 00:00:00
abstract::Profound alterations in host cell nuclear architecture accompany the lytic phase of Epstein-Barr virus (EBV) infection. Viral replication compartments assemble, host chromatin marginalizes to the nuclear periphery, cytoplasmic poly(A)-binding protein translocates to the nucleus, and polyadenylated mRNAs are sequestere...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01254-18
更新日期:2018-09-26 00:00:00
abstract::The experimental infection of newborn calves with bovine norovirus was used as a homologous large animal model to study the pathogenesis of norovirus infection and to determine target cells for viral replication. Six newborn calves were inoculated orally with Jena virus (JV), a bovine norovirus GIII.1 strain, and six ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.05342-11
更新日期:2011-11-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.3.2365-2375.1999
更新日期:1999-03-01 00:00:00
abstract::To examine the cell fusion activity of hepatitis C virus (HCV) envelope proteins (E1 and E2), we have established a sensitive cell fusion assay based on the activation of a reporter gene as described previously (O. Nussbaum, C. C. Broder, and E. A. Berger, J. Virol. 68:5411-5422, 1994). The chimeric HCV E1 and E2 prot...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.11.5066-5074.2000
更新日期:2000-06-01 00:00:00
abstract::Recently, efficient and long-term in vivo gene transfer by recombinant adeno-associated virus type 2 (rAAV) vectors has been demonstrated in a variety of tissues. Further improvement in vector titer and purity will expedite this in vivo exploration and provide preclinical information required for use in human gene the...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.3.2224-2232.1998
更新日期:1998-03-01 00:00:00
abstract::Mouse mammary tumor virus (MMTV)-induced mammary adenocarcinomas can develop from several different premalignant precursors common in GR mice. Insertion mutagenesis of the mammary protooncogenes int-1 and int-2 was studied in this multistep system by analyzing samples from various stages of neoplastic development for ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.64.4.1794-1802.1990
更新日期:1990-04-01 00:00:00
abstract::We have developed a means to identify genes associated with particular aspects of virulence. By beginning with an avirulent deletion mutant of rabbitpox virus and systematically reintroducing overlapping segments of the deleted region, we have identified two regions of the viral genome associated with increased virule...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.3.1530-1542.1991
更新日期:1991-03-01 00:00:00
abstract::Coxsackievirus B3 (CVB3) is an enterovirus in the family Picornaviridae that is significant to human health, being associated with myocarditis, aseptic meningitis, and pancreatitis, among other conditions. In addition to humans, Sichuan snub-nosed monkeys can be infected and killed by CVB3. Here, we report the first c...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02365-12
更新日期:2012-12-01 00:00:00
abstract::The insertion of a particular phi X DNA sequence in the plasmid pACYC177 strongly decreased the capacity of Escherichia coli cells containing such a plasmid to propagate bacteriophage phi X174. The smallest DNA sequence tested that showed the effect was the HindII fragment R4. This fragment does not code for a complet...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.42.1.1-11.1982
更新日期:1982-04-01 00:00:00