Vaccinia Virus Attenuation by Codon Deoptimization of the A24R Gene for Vaccine Development.
Vaccinia Virus Attenuation by Codon Deoptimization of the A24R Gene for Vaccine Development.
复制标题
DOI：
10.1128/spectrum.00272-22
复制
发表时间：
2022-06-29
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
痘病毒有很大的DNA基因组，它们能够感染包括人类在内的多种脊椎动物和无脊椎动物。尽管天花已被根除，但天花病毒感染仍然是一个重大的公共卫生问题。痘苗病毒(VV)是痘病毒科的典型成员，已被广泛应用于多种疾病的预防，包括多种传染病疫苗的研制和/或溶瘤治疗。已经进行了许多尝试来开发具有改进的安全性的新型减毒VV形式，以将其实施为疫苗和/或疫苗载体。我们和其他人以前已经证明了编码密码子去优化的病毒基因的RNA病毒是如何被减毒、免疫原性的，并且能够在一次给药后保护自己免受亲本病毒的挑战。在这项研究中，我们使用了相同的实验方法，基于使用错误表达的密码子来产生编码密码子去优化的A24R基因的重组(R)VV，该基因是病毒RNA聚合酶的关键成分。与我们之前对RNA病毒的研究类似，A24R密码子去优化的rVV(v-A24cd)在体内高度减毒，但在单次鼻腔给药后，能够保护免受亲本VV的致命挑战。这些结果表明，通过同义密码子去优化可以有效地减毒痘病毒，并为单独使用这种方法或与其他实验方法结合开发治疗痘病毒感染的减毒疫苗或产生改进的VV载体提供了可能性。此外，这种方法也可以应用于其他DNA病毒。重要性痘病毒科包括多种与医学和兽医相关的病毒，牛痘病毒(VV)是该家族的原型成员。VV在天花疫苗接种运动中用于根除天花病毒(VARV)，这种病毒被认为是可信的生物恐怖主义威胁。由于基因工程和疫苗技术的新创新，VV已成为一种流行的病毒载体，用于开发针对多种传染病的疫苗。已经使用了几种方法来产生减毒VV，用于将其实施为疫苗和/或疫苗载体。在这里，我们产生了一个包含密码子去优化的A24R基因(v-A24cd)的rVV，它编码病毒RNA聚合酶的一个关键成分。V-A24cd在培养细胞中稳定，在体内高度减毒，但能够抵抗亲本VV随后的致命攻击。我们的发现支持使用这种方法来开发安全、稳定和保护性的减毒活病毒和/或疫苗载体。
Poxviruses have large DNA genomes, and they are able to infect multiple vertebrate and invertebrate animals, including humans. Despite the eradication of smallpox, poxvirus infections still remain a significant public health concern. Vaccinia virus (VV) is the prototypic member in the poxviridae family and it has been used extensively for different prophylactic applications, including the generation of vaccines against multiple infectious diseases and/or for oncolytic treatment. Many attempts have been pursued to develop novel attenuated forms of VV with improved safety profiles for their implementation as vaccines and/or vaccines vectors. We and others have previously demonstrated how RNA viruses encoding codon-deoptimized viral genes are attenuated, immunogenic and able to protect, upon a single administration, against challenge with parental viruses. In this study, we employed the same experimental approach based on the use of misrepresented codons for the generation of a recombinant (r)VV encoding a codon-deoptimized A24R gene, which is a key component of the viral RNA polymerase. Similar to our previous studies with RNA viruses, the A24R codon-deoptimized rVV (v-A24cd) was highly attenuated in vivo but able to protect, after a single intranasal dose administration, against an otherwise lethal challenge with parental VV. These results indicate that poxviruses can be effectively attenuated by synonymous codon deoptimization and open the possibility of using this methodology alone or in combination with other experimental approaches for the development of attenuated vaccines for the treatment of poxvirus infection, or to generate improved VV-based vectors. Moreover, this approach could be applied to other DNA viruses. IMPORTANCE The family poxviridae includes multiple viruses of medical and veterinary relevance, being vaccinia virus (VV) the prototypic member in the family. VV was used during the smallpox vaccination campaign to eradicate variola virus (VARV), which is considered a credible bioterrorism threat. Because of novel innovations in genetic engineering and vaccine technology, VV has gained popularity as a viral vector for the development of vaccines against several infectious diseases. Several approaches have been used to generate attenuated VV for its implementation as vaccine and/or vaccine vector. Here, we generated a rVV containing a codon-deoptimized A24R gene (v-A24cd), which encodes a key component of the viral RNA polymerase. v-A24cd was stable in culture cells and highly attenuated in vivo but able to protect against a subsequent lethal challenge with parental VV. Our findings support the use of this approach for the development of safe, stable, and protective live-attenuated VV and/or vaccine vectors.
登录
查看更多内容
影响因子：
5.4
作者：
Boulanger, D;Green, P;Skinner, MA
通讯作者：
Skinner, MA
影响因子：
14.9
作者：
GRANTHAM, R;GAUTIER, C;GOUY, M
通讯作者：
GOUY, M
DOI：
10.3390/v6072735
发表时间：
2014-07-17
期刊：
Viruses
影响因子：
--
作者：
Altenburg AF;Kreijtz JH;de Vries RD;Song F;Fux R;Rimmelzwaan GF;Sutter G;Volz A
通讯作者：
Volz A
影响因子：
5.4
作者：
Cheng, Benson Yee Hin;Ortiz-Riano, Emilio;Martinez-Sobrido, Luis
通讯作者：
Martinez-Sobrido, Luis
影响因子：
3.7
作者：
Hilimire, Thomas A.;Nogales, Aitor;Martinez-Sobrido, Luis
通讯作者：
Martinez-Sobrido, Luis