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Identification of the Mechanisms Causing Reversion to Virulence in an Attenuated SARS-CoV for the Design of a Genetically Stable Vaccine

Identifieur interne : 001303 ( Main/Exploration ); précédent : 001302; suivant : 001304

Identification of the Mechanisms Causing Reversion to Virulence in an Attenuated SARS-CoV for the Design of a Genetically Stable Vaccine

Auteurs : Jose M. Jimenez-Guarde O [Espagne] ; Jose A. Regla-Nava [Espagne] ; Jose L. Nieto-Torres [Espagne] ; Marta L. Dediego [Espagne] ; Carlos Casta O-Rodriguez [Espagne] ; Raul Fernandez-Delgado [Espagne] ; Stanley Perlman [États-Unis] ; Luis Enjuanes [Espagne]

Source :

RBID : PMC:4626112

Descripteurs français

English descriptors

Abstract

A SARS-CoV lacking the full-length E gene (SARS-CoV-∆E) was attenuated and an effective vaccine. Here, we show that this mutant virus regained fitness after serial passages in cell culture or in vivo, resulting in the partial duplication of the membrane gene or in the insertion of a new sequence in gene 8a, respectively. The chimeric proteins generated in cell culture increased virus fitness in vitro but remained attenuated in mice. In contrast, during SARS-CoV-∆E passage in mice, the virus incorporated a mutated variant of 8a protein, resulting in reversion to a virulent phenotype. When the full-length E protein was deleted or its PDZ-binding motif (PBM) was mutated, the revertant viruses either incorporated a novel chimeric protein with a PBM or restored the sequence of the PBM on the E protein, respectively. Similarly, after passage in mice, SARS-CoV-∆E protein 8a mutated, to now encode a PBM, and also regained virulence. These data indicated that the virus requires a PBM on a transmembrane protein to compensate for removal of this motif from the E protein. To increase the genetic stability of the vaccine candidate, we introduced small attenuating deletions in E gene that did not affect the endogenous PBM, preventing the incorporation of novel chimeric proteins in the virus genome. In addition, to increase vaccine biosafety, we introduced additional attenuating mutations into the nsp1 protein. Deletions in the carboxy-terminal region of nsp1 protein led to higher host interferon responses and virus attenuation. Recombinant viruses including attenuating mutations in E and nsp1 genes maintained their attenuation after passage in vitro and in vivo. Further, these viruses fully protected mice against challenge with the lethal parental virus, and are therefore safe and stable vaccine candidates for protection against SARS-CoV.


Url:
DOI: 10.1371/journal.ppat.1005215
PubMed: 26513244
PubMed Central: 4626112


Affiliations:


Links toward previous steps (curation, corpus...)


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<term>Viral Vaccines</term>
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<p>A SARS-CoV lacking the full-length E gene (SARS-CoV-∆E) was attenuated and an effective vaccine. Here, we show that this mutant virus regained fitness after serial passages in cell culture or
<italic>in vivo</italic>
, resulting in the partial duplication of the membrane gene or in the insertion of a new sequence in gene 8a, respectively. The chimeric proteins generated in cell culture increased virus fitness
<italic>in vitro</italic>
but remained attenuated in mice. In contrast, during SARS-CoV-∆E passage in mice, the virus incorporated a mutated variant of 8a protein, resulting in reversion to a virulent phenotype. When the full-length E protein was deleted or its PDZ-binding motif (PBM) was mutated, the revertant viruses either incorporated a novel chimeric protein with a PBM or restored the sequence of the PBM on the E protein, respectively. Similarly, after passage in mice, SARS-CoV-∆E protein 8a mutated, to now encode a PBM, and also regained virulence. These data indicated that the virus requires a PBM on a transmembrane protein to compensate for removal of this motif from the E protein. To increase the genetic stability of the vaccine candidate, we introduced small attenuating deletions in E gene that did not affect the endogenous PBM, preventing the incorporation of novel chimeric proteins in the virus genome. In addition, to increase vaccine biosafety, we introduced additional attenuating mutations into the nsp1 protein. Deletions in the carboxy-terminal region of nsp1 protein led to higher host interferon responses and virus attenuation. Recombinant viruses including attenuating mutations in E and nsp1 genes maintained their attenuation after passage
<italic>in vitro</italic>
and
<italic>in vivo</italic>
. Further, these viruses fully protected mice against challenge with the lethal parental virus, and are therefore safe and stable vaccine candidates for protection against SARS-CoV.</p>
</div>
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<name sortKey="Peng, J" uniqKey="Peng J">J Peng</name>
</author>
<author>
<name sortKey="Wang, Z" uniqKey="Wang Z">Z Wang</name>
</author>
<author>
<name sortKey="Lu, H" uniqKey="Lu H">H Lu</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<affiliations>
<list>
<country>
<li>Espagne</li>
<li>États-Unis</li>
</country>
<region>
<li>Communauté de Madrid</li>
<li>Iowa</li>
</region>
<settlement>
<li>Iowa City</li>
<li>Madrid</li>
</settlement>
<orgName>
<li>Université autonome de Madrid</li>
<li>Université de l'Iowa</li>
</orgName>
</list>
<tree>
<country name="Espagne">
<region name="Communauté de Madrid">
<name sortKey="Jimenez Guarde O, Jose M" sort="Jimenez Guarde O, Jose M" uniqKey="Jimenez Guarde O J" first="Jose M." last="Jimenez-Guarde O">Jose M. Jimenez-Guarde O</name>
</region>
<name sortKey="Casta O Rodriguez, Carlos" sort="Casta O Rodriguez, Carlos" uniqKey="Casta O Rodriguez C" first="Carlos" last="Casta O-Rodriguez">Carlos Casta O-Rodriguez</name>
<name sortKey="Dediego, Marta L" sort="Dediego, Marta L" uniqKey="Dediego M" first="Marta L." last="Dediego">Marta L. Dediego</name>
<name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name>
<name sortKey="Fernandez Delgado, Raul" sort="Fernandez Delgado, Raul" uniqKey="Fernandez Delgado R" first="Raul" last="Fernandez-Delgado">Raul Fernandez-Delgado</name>
<name sortKey="Nieto Torres, Jose L" sort="Nieto Torres, Jose L" uniqKey="Nieto Torres J" first="Jose L." last="Nieto-Torres">Jose L. Nieto-Torres</name>
<name sortKey="Regla Nava, Jose A" sort="Regla Nava, Jose A" uniqKey="Regla Nava J" first="Jose A." last="Regla-Nava">Jose A. Regla-Nava</name>
</country>
<country name="États-Unis">
<region name="Iowa">
<name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name>
</region>
</country>
</tree>
</affiliations>
</record>

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