GENETIC AND CELLULAR MECHANISMS UNDERLYING RESISTANCE TO GAMMAHERPESVIRUS INFECTION - PROJECT SUMMARY CHRONIC INFECTION WITH THE GAMMAHERPESVIRUS EPSTEIN-BARR VIRUS (EBV) REPRESENTS A RISK FACTOR FOR SEVERAL CANCERS AND AUTOIMMUNE DISEASES. HOWEVER, THE ROLE OF HOST GENETIC VARIATION IN THE REGULATION OF IMMUNE RESPONSES TO CHRONIC GAMMAHERPESVIRUS INFECTION AND CONTROL OF VIRAL REPLICATION REMAINS UNCLEAR. WE PREVIOUSLY IDENTIFIED THE WILD-DERIVED MOUSE STRAIN PWD/PHJ (PWD) TO HAVE SUPERIOR CONTROL OF VIRAL LOAD COMPARED TO C57BL/6J (B6) MICE AT BOTH EARLY AND LATE TIME POINTS DURING INFECTION WITH MHV-68, A MURINE GAMMAHERPESVIRUS HOMOLOGOUS TO EBV. TO FURTHER EXAMINE THE ROLE OF HOST GENETICS ON GAMMAHERPESVIRUS INFECTION OUTCOMES, WE COMPLETED A GENETIC SCREEN OF C57BL/6J-CHRPWD CHROMOSOME SUBSTITUTION (CONSOMIC) MICE AND IDENTIFIED C57BL/6J-CHR17PWD (CHR17FPWD) CONSOMIC MICE AS A STRAIN HAVING SUPERIOR VIRAL CONTROL COMPARED TO B6 MICE. WE FURTHER NARROWED THE LOCUS ON CHR 17 TO AN INTERVAL AT 27.6-49.4 MB, WHICH INCLUDES THE MHC LOCUS. THE FOCUS OF THIS PROPOSAL IS TO 1) REFINE THE CHR 17 LOCUS REGULATING MHV-68 CONTROL AND 2) INVESTIGATE THE DYNAMICS OF MHV-68 B CELL INFECTION AND LATENCY IN GENETICALLY RESISTANT HOSTS. IN DIRECT SUPPORT OF THE PROPOSED STUDIES, THE TRAINING PLAN WILL DEVELOP KNOWLEDGE, EXPERTISE, SCIENTIFIC COMMUNICATION SKILLS, AND TECHNICAL ABILITIES IN 1) USING FORWARD GENETICS TO ESTABLISH NOVEL MOUSE MODELS OF GAMMAHERPESVIRUS INFECTION, 2) IMMUNOLOGY, WITH A FOCUS ON B CELL AND GERMINAL CENTER DYNAMICS, AND 3) BIOINFORMATICS WITH A FOCUS ON GENETIC MAPPING VIA QUANTITATIVE TRAIT LOCUS ANALYSIS. THE TRAINING ENVIRONMENT AT THE UNIVERSITY OF VERMONT (UVM) IS IDEALLY SUITED TO SUPPORT THIS PROPOSAL AS IT FOSTERS INTERDISCIPLINARY COLLABORATION, PROVIDES ACCESS TO STATE-OF-THE-ART FACILITIES, AND STRESSES ACTIVE MENTORSHIP.