DNA Immunization Using The Highly Conserved Murine Cytomegalovirus Genes Encoding The Homologs of Human Cytomegalovirus UL54 (DNA Polymerase) and UL105 (Helicase) Elicits Strong CD8 T Responses and Is Protective Against Systemic Challenge

Department of Cellular and Molecular Medicine, Division of Biological Sciences and Center for Molecular Genetics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0712; and Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239

^* To whom correspondence should be addressed. Email: dspector{at}ucsd.edu.

	Abstract

Human cytomegalovirus (HCMV) establishes a lifelong infection with the potential for reinfection or viral transmission even in the presence of strong and diverse CD8 T lymphocyte responses. This suggests that the CMVs skew the host T cell response in order to favor viral persistence. In this report, we hypothesized that the essential, nonstructural proteins that are highly conserved among the CMVs may represent a novel class of T cell targets for vaccine-mediated protection due to their requirements for expression and sequence stability, but that the observed subdominance of these antigens in the CMV infected host results from the virus limiting the T cell responses to otherwise protective specificities. We found that DNA immunization of mice with the MCMV homologs of HCMV DNA polymerase (M54) or helicase (M105) was protective against virus replication in the spleen following systemic challenge, with the protection level elicited by the M54 DNA being comparable to DNA expressing the immunodominant IE1-pp89. Intracellular interferon gamma staining of CD8 T cells from mice immunized with either the M54 or M105 DNAs showed strong primary responses that recalled rapidly after viral challenge. M54- and M105-specific CD8 T cells were detected after primary MCMV infection, but their levels were not consistently above background. The conserved, essential proteins of the CMVs thus represent a novel class of CD8 T cell targets that may contribute to a successful HCMV vaccine strategy.