Antibiotic-dependent expression of early transcription factor subunits leads to stringent control of vaccinia virus replication
Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved..
The use of vaccinia virus (VACV) as the vaccine against variola virus resulted in the eradication of smallpox. VACV has since been used in the development of recombinant vaccine and therapeutic vectors, but complications associated with uncontrolled viral replication have constrained its use as a live viral vector. We propose to improve the safety of VACV as a live-replicating vector by using elements of the tet operon to control the transcription of genes that are essential for viral growth. Poxviruses encode all enzymes and factors necessary for their replication within the host cell cytoplasm. One essential VACV factor is the vaccinia early transcription factor (VETF) packaged into the viral core. This heterodimeric protein is required for expression of early VACV genes. VETF is composed of a large subunit encoded by the A7L gene and a small subunit encoded by the D6R gene. Two recombinant VACVs were generated in which either the A7L or D6R gene was placed under the control of tet operon elements to allow their transcription, and therefore viral replication, to be dependent on tetracycline antibiotics such as doxycycline. In the absence of inducers, no plaques were produced but abortively infected cells could be identified by expression of a reporter gene. In the presence of doxycycline, both recombinant viruses replicated indistinguishably from the wild-type strain. This stringent control of VACV replication can be used for the development of safer, next-generation VACV vaccines and therapeutic vectors. Such replication-inducible VACVs would only replicate when administered with tetracycline antibiotics, and if adverse events were to occur, treatment would be as simple as antibiotic cessation.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2014 |
|---|---|
| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:181 |
|---|---|
| Enthalten in: |
Virus research - 181(2014) vom: 06. März, Seite 43-52 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Hagen, Caitlin J [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 29.10.2014 Date Revised 10.12.2019 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.virusres.2013.12.033 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM234197935 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM234197935 | ||
| 003 | DE-627 | ||
| 005 | 20231224100744.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2014 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.virusres.2013.12.033 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0780.xml |
| 035 | |a (DE-627)NLM234197935 | ||
| 035 | |a (NLM)24394294 | ||
| 035 | |a (PII)S0168-1702(13)00479-6 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Hagen, Caitlin J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Antibiotic-dependent expression of early transcription factor subunits leads to stringent control of vaccinia virus replication |
| 264 | 1 | |c 2014 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 29.10.2014 | ||
| 500 | |a Date Revised 10.12.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a The use of vaccinia virus (VACV) as the vaccine against variola virus resulted in the eradication of smallpox. VACV has since been used in the development of recombinant vaccine and therapeutic vectors, but complications associated with uncontrolled viral replication have constrained its use as a live viral vector. We propose to improve the safety of VACV as a live-replicating vector by using elements of the tet operon to control the transcription of genes that are essential for viral growth. Poxviruses encode all enzymes and factors necessary for their replication within the host cell cytoplasm. One essential VACV factor is the vaccinia early transcription factor (VETF) packaged into the viral core. This heterodimeric protein is required for expression of early VACV genes. VETF is composed of a large subunit encoded by the A7L gene and a small subunit encoded by the D6R gene. Two recombinant VACVs were generated in which either the A7L or D6R gene was placed under the control of tet operon elements to allow their transcription, and therefore viral replication, to be dependent on tetracycline antibiotics such as doxycycline. In the absence of inducers, no plaques were produced but abortively infected cells could be identified by expression of a reporter gene. In the presence of doxycycline, both recombinant viruses replicated indistinguishably from the wild-type strain. This stringent control of VACV replication can be used for the development of safer, next-generation VACV vaccines and therapeutic vectors. Such replication-inducible VACVs would only replicate when administered with tetracycline antibiotics, and if adverse events were to occur, treatment would be as simple as antibiotic cessation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Antibiotics | |
| 650 | 4 | |a Safety | |
| 650 | 4 | |a Vaccines and therapeutic vectors | |
| 650 | 4 | |a Vaccinia early transcription factor | |
| 650 | 4 | |a Vaccinia virus | |
| 650 | 4 | |a Viral vectors | |
| 650 | 7 | |a Anti-Bacterial Agents |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Viral Proteins |2 NLM | |
| 650 | 7 | |a early transcription factor protein, Vaccinia virus |2 NLM | |
| 650 | 7 | |a Tetracycline |2 NLM | |
| 650 | 7 | |a F8VB5M810T |2 NLM | |
| 700 | 1 | |a Titong, Allison |e verfasserin |4 aut | |
| 700 | 1 | |a Sarnoski, Ethan A |e verfasserin |4 aut | |
| 700 | 1 | |a Verardi, Paulo H |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Virus research |d 1984 |g 181(2014) vom: 06. März, Seite 43-52 |w (DE-627)NLM01292136X |x 1872-7492 |7 nnns |
| 773 | 1 | 8 | |g volume:181 |g year:2014 |g day:06 |g month:03 |g pages:43-52 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.virusres.2013.12.033 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 181 |j 2014 |b 06 |c 03 |h 43-52 | ||