Skip to main content
NCBI home page
Virologica Sinica logoLink to Virologica Sinica
. 2017 Sep 29;32(5):404–414. doi: 10.1007/s12250-017-3947-1

Attenuated phenotypes and analysis of a herpes simplex virus 1 strain with partial deletion of the UL7, UL41 and LAT genes

Xingli Xu 1,#, Yingqiu Guo 1,#, Shengtao Fan 1, Pingfang Cui 1, Min Feng 1, Lichun Wang 1, Ying Zhang 1, Yun Liao 1, Xiaolong Zhang 1, Qihan Li 1,✉
PMCID: PMC6598894  PMID: 28971351

Abstract

We previously constructed a herpes simplex virus 1 (HSV-1) UL7 mutant virus (M1) and showed that a partial deletion mutation of the UL7 gene led to a lower proliferative rate and an attenuated phenotype. Using the M1 mutant, we further modified the UL41 gene, which encodes another tegument protein, and the latency-associated transcript (LAT) gene. Observations of the resulting mutants with modified UL7 and UL41 (M2) or UL7, UL41 and LAT (M3) genes indicated attenuated phenotypes, with lower proliferative ratios in various cells, non-lethal infections in mice and lower viral loads in nervous tissues compared with the wild-type strain. Furthermore, no LAT stable intron could be detected in the trigeminal ganglion of M3-infected animals. The results obtained with the three HSV-1 mutants indicate that the M3 mutant is an attenuated strain with low pathogenicity during both acute and latent infections. Together, the results support the use of the M3 mutant as a candidate for the development of an HSV-1 vaccine. graphic file with name 12250_2017_3947_Fig1_HTML.jpg

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s12250-017-3947-1 and is accessible for authorized users.

Keywords: herpes simplex virus 1 (HSV-1), UL7, UL41, LAT, mutant

Electronic supplementary material

12250_2017_3947_MOESM1_ESM.pdf (2.3MB, pdf)

Attenuated phenotypes and analysis of a herpes simplex virus 1 strain with partial deletion of the UL7, UL41 and LAT genes

Acknowledgments

This work was supported by the National Basic Research Program (2012CB518901), Chinese academy of medical sciences (CAMS) Initiative for Innovative Medicine (2016-I2M-1-019), the National Natural Science Foundation of China (31300143, 31100127), and the Fundamental Research Funds for the Central Universities (2016ZX310047, 2016ZX350072). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Footnotes

These authors contributed equally to this work.

Change history

11/19/2021

A Correction to this paper has been published: 10.1007/s12250-021-00467-8

References

  1. Aranda AM, Epstein AL. Herpes simplex virus type 1 latency and reactivation: an update. Med Sci (Paris) 2015;31:506–514. doi: 10.1051/medsci/20153105012. [DOI] [PubMed] [Google Scholar]
  2. Augustinova H, Hoeller D, Yao F. The dominant-negative herpes simplex virus type 1 (HSV-1) recombinant CJ83193 can serve as an effective vaccine against wild-type HSV-1 infection in mice. J Virol. 2004;78:5756–5765. doi: 10.1128/JVI.78.11.5756-5765.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Awasthi S, Lubinski JM, Eisenberg RJ, Cohen GH, Friedman HM. An HSV-1 gD mutant virus as an entry-impaired live virus vaccine. Vaccine. 2008;26:1195–1203. doi: 10.1016/j.vaccine.2007.12.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. BenMohamed L, Osorio N, Srivastava R, Khan AA, Simpson JL, Wechsler SL. Decreased reactivation of a herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) mutant using the in vivo mouse UV-B model of induced reactivation. J Neurovirol. 2015;21:508–517. doi: 10.1007/s13365-015-0348-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brehm M, Samaniego LA, Bonneau RH, DeLuca NA, Tevethia SS. Immunogenicity of herpes simplex virus type 1 mutants containing deletions in one or more alpha-genes: ICP4, ICP27, ICP22, and ICP0. Virology. 1999;256:258–269. doi: 10.1006/viro.1999.9653. [DOI] [PubMed] [Google Scholar]
  6. Cotter CR, Nguyen ML, Yount JS, López CB, Blaho JA, Moran TM. The virion host shut-off (vhs) protein blocks a TLRindependent pathway of herpes simplex virus type 1 recognition in human and mouse dendritic cells. PLoS One. 2010;5:e8684. doi: 10.1371/journal.pone.0008684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. David AT, Saied A, Charles A, Subramanian R, Chouljenko VN, Kousoulas KG. A herpes simplex virus 1 (McKrae) mutant lacking the glycoprotein K gene is unable to infect via neuronal axons and egress from neuronal cell bodies. MBio. 2012;3(e00144-e00112):e00144–00112. doi: 10.1128/mBio.00144-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dumitrascu OM, Mott KR, Ghiasi H. A comparative study of experimental mouse models of central nervous system demyelination. Gene Ther. 2014;21:599–608. doi: 10.1038/gt.2014.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Farrell MJ, Dobson AT, Feldman LT. Herpes simplex virus latency-associated transcript is a stable intron. Proc Natl Acad Sci USA. 1991;88:790–794. doi: 10.1073/pnas.88.3.790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 2007;57:737–63. doi: 10.1016/j.jaad.2007.06.027. [DOI] [PubMed] [Google Scholar]
  11. Garland SM, Steben M. Genital herpes. Best Pract Res Clin Obstet Gynaecol. 2014;28:1098–1110. doi: 10.1016/j.bpobgyn.2014.07.015. [DOI] [PubMed] [Google Scholar]
  12. Herrera FJ, Triezenberg SJ. VP16-dependent association of chromatin-modifying coactivators and underrepresentation of histones at immediate-early gene promoters during herpes simplex virus infection. J Virol. 2004;78:9689–9696. doi: 10.1128/JVI.78.18.9689-9696.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Johnston C, Gottlieb SL, Wald A. Status of vaccine research and development of vaccines for herpes simplex virus. Vaccine. 2016;34:2948–2952. doi: 10.1016/j.vaccine.2015.12.076. [DOI] [PubMed] [Google Scholar]
  14. Kelly BJ, Fraefel C, Cunningham AL, Diefenbach RJ. Functional roles of the tegument proteins of herpes simplex virus type 1. Virus Res. 2009;145:173–186. doi: 10.1016/j.virusres.2009.07.007. [DOI] [PubMed] [Google Scholar]
  15. Koelle DM, Corey L. Recent progress in herpes simplex virus immunobiology and vaccine research. Clin Microbiol Rev. 2003;16:96–113. doi: 10.1128/CMR.16.1.96-113.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kukhanova MK, Korovina AN, Kochetkov SN. Human herpes simplex virus: life cycle and development of inhibitors. Biochemistry (Mosc) 2014;79:1635–1652. doi: 10.1134/S0006297914130124. [DOI] [PubMed] [Google Scholar]
  17. Lee K, Kolb AW, Larsen I, Craven M, Brandt CR. Mapping murine corneal neovascularization and weight loss virulence determinants in the herpes simplex virus 1 genome and the detection of an epistatic interaction between the UL and IRS/US regions. J Virol. 2016;90:8115–8131. doi: 10.1128/JVI.00821-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Leib DA, Bogard CL, Kosz-Vnenchak M, Hicks KA, Coen DM, Knipe DM, Schaffer PA. A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from thelatent state with reduced frequency. J Virol. 1989;63:2893–2900. doi: 10.1128/JVI.63.7.2893-2900.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Looker KJ, Magaret AS, May MT, Turner KM, Vickerman P, Gottlieb SL, Newman LM. Global and Regional Estimates of Prevalent and Incident Herpes Simplex Virus Type 1 Infections in 2012. PLoS One. 2015;10:e0140765. doi: 10.1371/journal.pone.0140765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Loret S, Lippé R. Biochemical analysis of infected cell polypeptide (ICP)0, ICP4, UL7 and UL23 incorporated into extracellular herpes simplex virus type 1 virions. J Gen Virol. 2012;93:624–634. doi: 10.1099/vir.0.039776-0. [DOI] [PubMed] [Google Scholar]
  21. Maggioncalda J, Mehta A, Fraser NW, Block TM. Analysis of a herpes simplex virus type 1 LAT mutant with a deletion between the putative promoter and the 5' end of the 2. 0-kilobase TranScript. J Virol. 1994;68:7816–7824. doi: 10.1128/jvi.68.12.7816-7824.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Morrison LA, Knipe DM. Contributions of antibody and T cell subsets to protection elicited by immunization with a replication-defective mutant of herpes simplex virus type 1. Virology. 1997;239:315–326. doi: 10.1006/viro.1997.8884. [DOI] [PubMed] [Google Scholar]
  23. Paludan SR, Bowie AG, Horan KA, Fitzgerald KA. Recognition of herpesviruses by the innate immune system. Nat Rev Immunol. 2011;11:143–154. doi: 10.1038/nri2937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8:2281–2308. doi: 10.1038/nprot.2013.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Read GS, Karr BM, Knight K. Isolation of a herpes simplex virus type 1 mutant with a deletion in the virion host shutoff gene and identification of multiple forms of the vhs (UL41) polypeptide. J Virol. 1993;67:7149–7160. doi: 10.1128/JVI.67.12.7149-7160.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Saffran HA, Read GS, Smiley JR. Evidence for translational regulation by the herpes simplex virus virion host shutoff protein. J Virol. 2010;84:6041–6049. doi: 10.1128/JVI.01819-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Samady L, Costigliola E, MacCormac L, McGrath Y, Cleverley S, Lilley CE, Smith J, Latchman DS, Chain B, Coffin RS. Deletion of the virion host shutoff protein (vhs) from herpes simplex virus (HSV) relieves the viral block to dendritic cell activation: potential of vhs-HSV vectors for dendritic cellmediated immunotherapy. J Virol. 2003;77:3768–3776. doi: 10.1128/JVI.77.6.3768-3776.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Samoto K, Perng GC, Ehtesham M, Liu Y, Wechsler SL, Nesburn AB, Black KL, Yu JS. A herpes simplex virus type 1 mutant deleted for gamma34.5 and LAT kills glioma cells in vitro and is inhibited for in vivo reactivation. Cancer Gene Ther. 2001;8:269–277. doi: 10.1038/sj.cgt.7700306. [DOI] [PubMed] [Google Scholar]
  29. Sawtell NM, Triezenberg SJ, Thompson RL. VP16 serine 375 is a critical determinant of herpes simplex virus exit from latency in vivo. J Neurovirol. 2011;17:546–551. doi: 10.1007/s13365-011-0065-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stanfield B, Kousoulas KG. Herpes Simplex Vaccines: Prospects of Live-attenuated HSV Vaccines to Combat Genital and Ocular infections. Curr Clin Microbiol Rep. 2015;2:125–136. doi: 10.1007/s40588-015-0020-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Strain AK, Rice SA. Phenotypic suppression of a herpes simplex virus 1 ICP27 mutation by enhanced transcription of the mutant gene. J Virol. 2011;85:5685–5690. doi: 10.1128/JVI.00315-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tanaka M, Sata T, Kawaguchi Y. The product of the herpes simplex virus 1 UL7 gene interacts with a mitochondrial protein, adenine nucleotide translocator 2. Virol J. 2008;5:125. doi: 10.1186/1743-422X-5-125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Thompson RL, Sawtell NM. The herpes simplex virus type 1 latency-associated transcript gene regulates the establishment of latency. J Virol. 1997;71:5432–5440. doi: 10.1128/JVI.71.7.5432-5440.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wagner EK, Flanagan WM, Devi-Rao G, Zhang YF, Hill JM, Anderson KP, Stevens JG. The herpes simplex virus latencyassociated transcript is spliced during the latent phase of infection. J Virol. 1988;62:4577–4585. doi: 10.1128/JVI.62.12.4577-4585.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, Berman SM, Markowitz LE. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296:964–973. doi: 10.1001/jama.296.8.964. [DOI] [PubMed] [Google Scholar]
  36. Xu X, Che Y, Li Q. HSV-1 tegument protein and the development of its genome editing technology. Virol J. 2016;13:108. doi: 10.1186/s12985-016-0563-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Xu X, Fan S, Zhou J, Zhang Y, Che Y, Cai H, Wang L, Guo L, Liu L, Li Q. The mutated tegument protein UL7 attenuates the virulence of herpes simplex virus 1 by reducing the modulation of alpha-4 gene transcription. Virol J. 2016;13:152. doi: 10.1186/s12985-016-0600-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Yu X, Liu L, Wu L, Wang L, Dong C, Li W, Li Q. Herpes simplex virus type 1 tegument protein VP22 is capable of modulating the transcription of viral TK and gC genes via interaction with viral ICP0. Biochimie. 2010;92:1024–1030. doi: 10.1016/j.biochi.2010.04.025. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

12250_2017_3947_MOESM1_ESM.pdf (2.3MB, pdf)

Attenuated phenotypes and analysis of a herpes simplex virus 1 strain with partial deletion of the UL7, UL41 and LAT genes

Articles from Virologica Sinica are provided here courtesy of Wuhan Institute of Virology, Chinese Academy of Sciences

RESOURCES