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Journal of Virology, January 2007, p. 791-799, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.00714-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Attenuation of Herpes Simplex Virus Neurovirulence with Picornavirus cis-Acting Genetic Elements{triangledown}

Stephanie A. Campbell,1 Matthew Mulvey,2 Ian Mohr,2 and Matthias Gromeier1*

Division of Neurological Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710,1 Department of Microbiology and NYU Cancer Institute, New York University School of Medicine, New York, New York 100162

Received 7 April 2006/ Accepted 23 October 2006

Viral pathogenesis depends on a suitable milieu in target host cells permitting viral gene expression, propagation, and spread. In many instances, viral genomes can be manipulated to select for propagation in certain tissues or cell types. This has been achieved for the neurotropic poliovirus (PV) by exchange of the internal ribosomal entry site (IRES), which is responsible for translation of the uncapped plus-strand RNA genome. The IRES of human rhinovirus type 2 (HRV2) confers neuron-specific replication deficits to PV but has no effect on viral propagation in malignant glioma cells. We report here that placing the critical {gamma}134.5 virulence genes of herpes simplex virus type 1 (HSV) under translation control of the HRV2 IRES results in neuroattenuation in mice. In contrast, IRES insertion permits HSV propagation in malignant glioma cell lines that do not support replication of HSV recombinants carrying {gamma}134.5 deletions. Our observations indicate that the conditions for alternative translation initiation at the HRV2 IRES in malignant glioma cells differ from those in normal central nervous system (CNS) cells. Picornavirus regulatory sequences mediating cell type-specific gene expression in the CNS can be utilized to target cancerous cells at the level of translation regulation outside their natural context.

* Corresponding author. Mailing address: Department of Surgery, Duke University Medical Center, Box 3020, Durham, NC 27710. Phone: (919) 668-6205. Fax: (919) 684-8735. E-mail: grome001{at}mc.duke.edu.

{triangledown} Published ahead of print on 1 November 2006.

Journal of Virology, January 2007, p. 791-799, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.00714-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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