THE PARAPOXVIRUS ORF VIRUS (ORFV) HAS LONG BEEN RECOGNIZED FOR ITS UNIQUE IMMUNOMODULATORY EFFECTS ON VARIOUS ANIMAL SPECIES, AND ORFV PREPARATIONS ARE USED IN VETERINARY MEDICINE AS A PREVENTIVE AND THERAPEUTIC IMMUNOMODULATORY AGENT. HOWEVER, THE FUNCTIONS (GENES, PROTEINS, AND MECHANISMS OF ACTION) EVOLVED BY ORFV TO MODULATE HOST IMMUNE RESPONSES ARE POORLY UNDERSTOOD. WE HAVE IDENTIFIED NOVEL ORFV GENES WITH PUTATIVE VIRULENCE AND IMMUNOMODULATORY FUNCTIONS THAT LACK SIMILARITY TO OTHER VIRAL OR CELLULAR PROTEINS. WE HYPOTHESIZE THESE ORFV GENES ENCODE FOR NOVEL IMMUNOMODULATORY PROTEINS (IMPS).THE OBJECTIVES OF THIS STUDY ARE TO: 1) IDENTIFY NOVEL IMPS OF ORFV AND,DETERMINE THE MOLECULAR MECHANISM(S) BY WHICH ORFV IMPS INTERFERE WITH IMMUNE SIGNALING PATHWAYS AND2)DETERMINE FUNCTION(S) OF ORFV IMPS IN THE NATURAL HOST, INCLUDING ASSESSMENT OF ORFV IMP GENE-DELETED VIRUSES FOR VACCINE VECTOR POTENTIAL.WE ANTICIPATE THAT SUCCESSFUL COMPLETION OF THESE STUDIES WILL HAVE BROAD IMPACT ON IMMUNOVIROLOGY AND ON CURRENT UNDERSTANDING OF THE IMMUNOMODULATORY PROPERTIES OF ORFV. THE WORK WILL IDENTIFY AND CHARACTERIZE PROTEINS WITH NOVEL AND BROAD BASED IMMUNOMODULATORY ACTIVITIES SUITABLE FOR USE IN A VARIETY OF ANIMAL SPECIES POTENTIALLY OFFERING ADVANTAGES OVER EXISTING IMMUNOTHERAPIES AND POSITIVELY IMPACTING FORMULATION OF IMPROVED VACCINES, VACCINE VECTORS AND ADJUVANTS. IN ADDITION, AN IMPROVED UNDERSTANDING OF NOVEL VIRAL IMMUNOMODULATORY FUNCTIONS AND HOST RESPONSES IN THE SKIN MAY SUGGEST NEW AND IMPROVED STRATEGIES FOR CONTROLLING VIRAL AND OTHER DISEASES TARGETING SKIN AND MUCOSAL SURFACES.