Analysis of IE62 mutations found in Varicella-Zoster virus vaccine strains for transactivation activity

Hyemin Ko, Gwang Myeong Lee, Ok Shin, Moon Jung Song, Chan Hee Lee, Young Eui Kim, Jin Hyun Ahn

Research output: Contribution to journalArticle

Abstract

Live attenuated vaccine strains have been developed for Varicella-Zoster virus (VZV). Compared to clinically isolated strains, the vaccine strains contain several non-synonymous mutations in open reading frames (ORFs) 0, 6, 31, 39, 55, 62, and 64. In particular, ORF62, encoding an immediate-early (IE) 62 protein that acts as a transactivator for viral gene expression, contains six non-synonymous mutations, but whether these mutations affect transactivation activity of IE62 is not understood. In this study, we investigated the role of non-synonymous vaccine-type mutations (M99T, S628G, R958G, V1197A, I1260V, and L1275S) of IE62 in Suduvax, a vaccine strain isolated in Korea, for transactivation activity. In reporter assays, Suduvax IE62 showed 2- to 4-fold lower transactivation activity toward ORF4, ORF28, ORF29, and ORF68 promoters than wild-type IE62. Introduction of individual M99T, S628G, R958G, or V1197A/I1260V/L1275S mutations into wild-type IE62 did not affect transactivation activity. However, the combination of M99T within the N-terminal Sp transcription factor binding region and V1197A/I1260V/L1275S within the C-terminal serine-enriched acidic domain (SEAD) significantly reduced the transactivation activity of IE62. The M99T/V1197A/I1260V/L1275S mutant IE62 did not show considerable alterations in intracellular distribution and Sp3 binding compared to wild-type IE62, suggesting that other alteration(s) may be responsible for the reduced transactivation activity. Collectively, our results suggest that acquisition of mutations in both Met 99 and the SEAD of IE62 is responsible for the reduced transactivation activity found in IE62 of the VZV vaccine strains and contributes to attenuation of the virus.

Original languageEnglish
Pages (from-to)441-448
Number of pages8
JournalJournal of Microbiology
Volume56
Issue number6
DOIs
Publication statusPublished - 2018 Jun 1

Fingerprint

Herpes Zoster Vaccine
Human Herpesvirus 3
Transcriptional Activation
Mutation
Vaccines
Serine
Sp Transcription Factors
Immediate-Early Proteins
Attenuated Vaccines
Trans-Activators
Viral Genes
Chickenpox
Korea
Open Reading Frames
Viruses
Gene Expression

Keywords

  • IE62
  • mutation
  • Suduvax
  • vaccine
  • Varicella-Zoster virus

ASJC Scopus subject areas

  • Microbiology
  • Applied Microbiology and Biotechnology

Cite this

Analysis of IE62 mutations found in Varicella-Zoster virus vaccine strains for transactivation activity. / Ko, Hyemin; Lee, Gwang Myeong; Shin, Ok; Song, Moon Jung; Lee, Chan Hee; Kim, Young Eui; Ahn, Jin Hyun.

In: Journal of Microbiology, Vol. 56, No. 6, 01.06.2018, p. 441-448.

Research output: Contribution to journalArticle

Ko, Hyemin ; Lee, Gwang Myeong ; Shin, Ok ; Song, Moon Jung ; Lee, Chan Hee ; Kim, Young Eui ; Ahn, Jin Hyun. / Analysis of IE62 mutations found in Varicella-Zoster virus vaccine strains for transactivation activity. In: Journal of Microbiology. 2018 ; Vol. 56, No. 6. pp. 441-448.
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AU - Kim, Young Eui

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AB - Live attenuated vaccine strains have been developed for Varicella-Zoster virus (VZV). Compared to clinically isolated strains, the vaccine strains contain several non-synonymous mutations in open reading frames (ORFs) 0, 6, 31, 39, 55, 62, and 64. In particular, ORF62, encoding an immediate-early (IE) 62 protein that acts as a transactivator for viral gene expression, contains six non-synonymous mutations, but whether these mutations affect transactivation activity of IE62 is not understood. In this study, we investigated the role of non-synonymous vaccine-type mutations (M99T, S628G, R958G, V1197A, I1260V, and L1275S) of IE62 in Suduvax, a vaccine strain isolated in Korea, for transactivation activity. In reporter assays, Suduvax IE62 showed 2- to 4-fold lower transactivation activity toward ORF4, ORF28, ORF29, and ORF68 promoters than wild-type IE62. Introduction of individual M99T, S628G, R958G, or V1197A/I1260V/L1275S mutations into wild-type IE62 did not affect transactivation activity. However, the combination of M99T within the N-terminal Sp transcription factor binding region and V1197A/I1260V/L1275S within the C-terminal serine-enriched acidic domain (SEAD) significantly reduced the transactivation activity of IE62. The M99T/V1197A/I1260V/L1275S mutant IE62 did not show considerable alterations in intracellular distribution and Sp3 binding compared to wild-type IE62, suggesting that other alteration(s) may be responsible for the reduced transactivation activity. Collectively, our results suggest that acquisition of mutations in both Met 99 and the SEAD of IE62 is responsible for the reduced transactivation activity found in IE62 of the VZV vaccine strains and contributes to attenuation of the virus.

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