This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chung, R. Y.
Right arrow Articles by Chiocca, E. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chung, R. Y.
Right arrow Articles by Chiocca, E. A.

 Previous Article  |  Next Article 

Journal of Virology, September 1999, p. 7556-7564, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

B-myb Promoter Retargeting of Herpes Simplex Virus gamma 34.5 Gene-Mediated Virulence toward Tumor and Cycling Cells

Richard Y. Chung, Yoshinaga Saeki, and E. Antonio Chiocca*

Molecular Neuro-Oncology Laboratories, Neurosurgical Service, Massachusetts General Hospital, Charlestown, Massachusetts 02129

Received 16 April 1999/Accepted 15 June 1999

Deletion of the gamma 34.5 gene coding for virulence markedly reduces cytotoxicity mediated by herpes simplex virus type 1 (HSV-1) (J. M. Markert et al., Neurosurgery 32:597-603, 1993; N. S. Markovitz et al., J. Virol. 71:5560-5569, 1997). To target lytic virulence to tumors, we have created a novel HSV-1 mutant, designated Myb34.5. This viral mutant is characterized by a deletion of the gene for infected cell polypeptide 6 (ICP6; also known as UL39 or ribonucleotide reductase) and of the two endogenous copies of the gamma 34.5 gene (RL1) and by reintroduction of one copy of gamma 34.5 under control of the E2F-responsive, cellular B-myb promoter. On direct intracerebral inoculation in BALB/c mice, the 50% lethal dose (LD50) for Myb34.5 was 2.7 × 107 PFU while that for HSVs with mutations in the gamma 34.5 gene could not be technically achieved with available viral stocks and it was estimated as >1 × 107 PFU. The LD50 for an HSV with a single defect in ICP6 function was 1.3 × 106 PFU. Conversely, Myb34.5's oncolytic efficacy against a variety of human glioma cells in culture and in vivo was enhanced compared to that of HSVs with gamma 34.5 mutations, and in fact, it was comparable to that of the wild-type F strain and of viral mutants that possess a wild-type gamma 34.5 gene. The characteristic shutoff of host protein synthesis, occurring after infection of human SK-N-SH neuroblastoma cells by gamma 34.5 mutant viruses (J. Chou and B. Roizman, Proc. Natl. Acad. Sci. USA 89:3266-3270, 1992), was not present after infection with Myb34.5. There was an increase of almost 3 logarithmic units in the production of progeny virus in arrested fibroblasts compared to that in cycling fibroblasts infected with Myb34.5. These results suggest that transcriptional regulation of gamma 34.5 by cell cycle-regulated promoters can be used to target HSV-1 virulence toward tumors while maintaining the desirable neuroattenuated phenotype of a gamma 34.5 mutant.

* Corresponding author. Mailing address: Molecular Neuro-Oncology Laboratories, Neurosurgical Service, Massachusetts General Hospital, Bldg. 149, 13th St., Charlestown, MA 02129. Phone: (617) 726-4684. Fax: (617) 726-5079. E-mail: chiocca{at}helix.mgh.harvard.edu.

Journal of Virology, September 1999, p. 7556-7564, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Adusumilli, P. S., Chan, M.-K., Hezel, M., Yu, Z., Stiles, B. M., Chou, T.-C., Rusch, V. W., Fong, Y. (2007). Radiation-Induced Cellular DNA Damage Repair Response Enhances Viral Gene Therapy Efficacy in the Treatment of Malignant Pleural Mesothelioma. Ann. Surg. Oncol. 14: 258-269 [Abstract] [Full Text]  
  • Li, H., Dutuor, A., Tao, L., Fu, X., Zhang, X. (2007). Virotherapy with a Type 2 Herpes Simplex Virus-Derived Oncolytic Virus Induces Potent Antitumor Immunity against Neuroblastoma. Clin. Cancer Res. 13: 316-322 [Abstract] [Full Text]  
  • Liu, T.-C., Zhang, T., Fukuhara, H., Kuroda, T., Todo, T., Canron, X., Bikfalvi, A., Martuza, R. L., Kurtz, A., Rabkin, S. D. (2006). Dominant-Negative Fibroblast Growth Factor Receptor Expression Enhances Antitumoral Potency of Oncolytic Herpes Simplex Virus in Neural Tumors.. Clin. Cancer Res. 12: 6791-6799 [Abstract] [Full Text]  
  • Adusumilli, P. S., Stiles, B. M., Chan, M.-K., Chou, T.-C., Wong, R. J., Rusch, V. W., Fong, Y. (2005). Radiation Therapy Potentiates Effective Oncolytic Viral Therapy in the Treatment of Lung Cancer. Ann. Thorac. Surg. 80: 409-417 [Abstract] [Full Text]  
  • Kambara, H., Okano, H., Chiocca, E. A., Saeki, Y. (2005). An Oncolytic HSV-1 Mutant Expressing ICP34.5 under Control of a Nestin Promoter Increases Survival of Animals even when Symptomatic from a Brain Tumor. Cancer Res. 65: 2832-2839 [Abstract] [Full Text]  
  • Chiocca, E. A. (2005). Oncolytic Viral Therapeutics Based on Herpes Simplex Virus Type I. aacredbook 2005: 139-140 [Full Text]  
  • Kasuya, H., Pawlik, T. M., Mullen, J. T., Donahue, J. M., Nakamura, H., Chandrasekhar, S., Kawasaki, H., Choi, E., Tanabe, K. K. (2004). Selectivity of an Oncolytic Herpes Simplex Virus for Cells Expressing the DF3/MUC1 Antigen. Cancer Res. 64: 2561-2567 [Abstract] [Full Text]  
  • Mullen, J. T., Tanabe, K. K. (2003). Viral Oncolysis for Malignant Liver Tumors. Ann. Surg. Oncol. 10: 596-605 [Abstract] [Full Text]  
  • Ichikawa, T., Chiocca, E. A. (2001). Comparative Analyses of Transgene Delivery and Expression in Tumors Inoculated with a Replication-conditional or -defective Viral Vector. Cancer Res. 61: 5336-5339 [Abstract] [Full Text]  
  • Taneja, S., MacGregor, J., Markus, S., Ha, S., Mohr, I. (2001). Enhanced antitumor efficacy of a herpes simplex virus mutant isolated by genetic selection in cancer cells. Proc. Natl. Acad. Sci. USA 10.1073/pnas.161011798v1 [Abstract] [Full Text]  
  • Mohr, I., Sternberg, D., Ward, S., Leib, D., Mulvey, M., Gluzman, Y. (2001). A Herpes Simplex Virus Type 1 {gamma}34.5 Second-Site Suppressor Mutant That Exhibits Enhanced Growth in Cultured Glioblastoma Cells Is Severely Attenuated in Animals. J. Virol. 75: 5189-5196 [Abstract] [Full Text]  
  • Jacobs, A., Tjuvajev, J. G., Dubrovin, M., Akhurst, T., Balatoni, J., Beattie, B., Joshi, R., Finn, R., Larson, S. M., Herrlinger, U., Pechan, P. A., Chiocca, E. A., Breakefield, X. O., Blasberg, R. G. (2001). Positron Emission Tomography-based Imaging of Transgene Expression Mediated by Replication-conditional, Oncolytic Herpes Simplex Virus Type 1 Mutant Vectors in Vivo. Cancer Res. 61: 2983-2995 [Abstract] [Full Text]  
  • Tan, S.-L., Katze, M. G. (2000). HSV.com: Maneuvering the internetworks of viral neuropathogenesis and evasion of the host defense. Proc. Natl. Acad. Sci. USA 97: 5684-5686 [Full Text]  
  • Ikeda, K., Wakimoto, H., Ichikawa, T., Jhung, S., Hochberg, F. H., Louis, D. N., Chiocca, E. A. (2000). Complement Depletion Facilitates the Infection of Multiple Brain Tumors by an Intravascular, Replication-Conditional Herpes Simplex Virus Mutant. J. Virol. 74: 4765-4775 [Abstract] [Full Text]  
  • Taneja, S., MacGregor, J., Markus, S., Ha, S., Mohr, I. (2001). Enhanced antitumor efficacy of a herpes simplex virus mutant isolated by genetic selection in cancer cells. Proc. Natl. Acad. Sci. USA 98: 8804-8808 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»