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A Replication-Deficient Murine -Herpesvirus Blocked in Late Viral Gene Expression Can Establish Latency and Elicit Protective Cellular Immunity¹

Basak Kayhan^*, Eric J. Yager^*, Kathleen Lanzer^*, Tres Cookenham^*, Qingmei Jia, Ting-Ting Wu, David L. Woodland^*, Ren Sun and Marcia A. Blackman^2,*

^* Trudeau Institute, Saranac Lake, NY 12983; and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095

The human -herpesviruses, EBV and Kaposi’s sarcoma-associated herpesvirus, are widely disseminated and are associated with the onset of a variety of malignancies. Thus, the development of prophylactic and therapeutic vaccination strategies is an important goal. The experimental mouse -herpesvirus, HV68 (or MHV-68), has provided an in vivo model for studying immune control of these persistent viruses. In the current studies, we have examined infectivity, immunogenicity, and protective efficacy following infection with a replication-deficient HV68 blocked in late viral gene expression, ORF31STOP. The data show that ORF31STOP was able to latently infect B cells. However, the anatomical site and persistence of the infection depended on the route of inoculation, implicating a role for viral replication in viral spread but not the infectivity per se. Furthermore, i.p. infection with ORF31STOP elicited strong cellular immunity but a non-neutralizing Ab response. In contrast, intranasal infection was poorly immunogenic. Consistent with this, mice infected i.p. had enhanced control of both the lytic and latent viral loads following challenge with wild-type HV68, whereas intranasal infected mice were not protected. These data provide important insight into mechanisms of infection and protective immunity for the -herpesviruses and demonstrate the utility of replication-deficient mutant viruses in direct testing of "proof of principal" vaccination strategies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI51602 and AI42927 (to M.A.B.), DE015752 and CA120761 (to R.S.), and the Trudeau Institute.

² Address correspondence and reprint requests to Dr. Marcia A. Blackman, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: mblackman{at}trudeauinstitute.org

³ Abbreviations used in this paper: dpi, days post infection; LDA/PCR, limiting dilution nested PCR assay; i.n., intranasal.

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