JVI Accepts, published online ahead of print on 3 October 2007

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J. Virol. doi:10.1128/JVI.01911-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

TARGETED DELETION OF REGIONS RICH IN IMMUNE EVASIVE GENES FROM THE CYTOMEGALOVIRUS GENOME AS NOVEL VACCINE STRATEGY

Luka iin-ain^*, Ivan Bubi, Margit Schnee, Zsolt Ruzsics, Christian Mohr, Stipan Jonji, and Ulrich H. Koszinowski

Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006; Max von Pettenkofer Institute, Ludwig Maximilians-University, 30886 Munich, Germany; Department of Histology and Embryology, Medical Faculty, University of Rijeka, 51000 Rijeka, Croatia

^* To whom correspondence should be addressed. Email: cicinsai{at}ohsu.edu.

Human cytomegalovirus (CMV), a ubiquitous human pathogen, is a leading cause of congenital infections, and represents a serious health risk for the immunosuppressed patient. A vaccine against CMV is currently not available. CMV is characterized by its large genome, and by multiple genes modulating the immunity of the host, which cluster predominantly at genome termini. Here we tested if the deletion of gene blocks rich in immunomodulatory genes could be used as a novel concept in the generation of immunogenic, but avirulent, herpesviral vaccines. To generate an experimental CMV vaccine, we selectively deleted 32 genes from the mouse cytomegalovirus (MCMV) genome. The resulting mutant grew to titers similar to wild-type (WT) MCMV in vitro. In vivo the mutant was 10,000-fold attenuated, and well tolerated, even by highly susceptible mice, deficient for B, T and NK-cells or for the interferon type I receptor. Equally relevant for safety concerns, immune suppression did not lead to its reactivation from latency. Immunization with the replication competent mutant, but not with inactivated virus, resulted in protective immunity, which increased over time. Vaccination induced MCMV-specific antibodies, and a strong T-cell response. We propose that a targeted and rational approach can improve future herpesviral vaccines and vaccine-vectors.