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Journal of Virology, June 2004, p. 5756-5765, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5756-5765.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Hanka Augustinova,{dagger} Daniela Hoeller,{dagger} and Feng Yao{dagger}*

Laboratory of Tissue Repair and Gene Transfer, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Received 11 September 2003/ Accepted 24 February 2004

By selectively regulating the expression of the trans-dominant-negative mutant polypeptide UL9-C535C, of herpes simplex virus type 1 (HSV-1) origin binding protein UL9 with the tetracycline repressor (tetR)-mediated gene switch, we recently generated a novel replication-defective and anti-HSV-specific HSV-1 recombinant, CJ83193. The UL9-C535C peptides expressed by CJ83193 can function as a potent intracellular therapy against its own replication, as well as the replication of wild-type HSV-1 and HSV-2 in coinfected cells. In this report, we demonstrate that CJ83193 cannot initiate acute productive infection in corneas of infected mice nor can it reactivate from trigeminal ganglia of mice latently infected by CJ83193 in a mouse ocular model. Given that CJ83193 is capable of expressing the viral {alpha}, ß, and {gamma}1 genes but little or no {gamma}2 genes, we tested the vaccine potential of CJ83193 against HSV-1 infection in a mouse ocular model. Our studies showed that immunization with CJ83193 significantly reduced the yields of challenge HSV in the eyes and trigeminal ganglia on days 3, 5, and 7 postchallenge. Like in mice immunized with the wild-type HSV-1 strain KOS, immunization of mice with CJ83193 prevents the development of keratitis and encephalitis induced by corneal challenge with wild-type HSV-1 strain mP. Delayed-type hypersensitivity (DTH) assays demonstrate that CJ83193 can elicit durable cell-mediated immunity at the same level as that of wild-type HSV-1 and is more effective than that induced by d27, an HSV-1 ICP27 deletion mutant. Moreover, mice immunized with CJ83193 developed strong, durable HSV-1-neutralizing antibodies at levels at least twofold higher than those induced by d27. The results presented in this report have shed new light on the development of effective HSV viral vaccines that encode a unique safety mechanism capable of inhibiting the mutant's own replication and that of wild-type virus.

* Corresponding author. Mailing address: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115. Phone: (617) 525-6868. Fax: (617) 278-6918. E-mail: fyao{at}rics.bwh.harvard.edu.

{dagger} H.A., D.H., and F.Y. contributed equally to this work.

Journal of Virology, June 2004, p. 5756-5765, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5756-5765.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.





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