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Viral and host genetic regulation of herpes simplex virus pathogenesis; a genomics squared approach
 RICHARD LEE THOMPSON, Ph.D. Associate ProfessorDepartment of Molecular Genetics, Biochemistry and Microbiology

University of Cincinnati College of Medicine, Cincinnati, OH

R.L. Thompson and N.M. SawtellThe severity and frequency of recurrent disease experienced varies widely in the human population, from none to multiple events per year and from asymptomatic shedding to fatal encephalitis.  What underlies these differences is not well understood, but a reasonable hypothesis is that the intersection of host and infecting viral genetics influences both primary and recurrent disease outcomes.  In order to begin to systematically test this hypothesis, we are deep phenotyping HSV-1 disease in the C57Bl/6xDba/2 advanced recombinant inbred strains (BXD ARI) and have identified two previously unknown resistance loci on chromosomes12 and 16.   Here we have utilized selected BXD strains that differ at these and other loci in combination with 14 low passage clinical isolates (CIs) and 4 common laboratory strains of HSV-1 to establish into if (and ultimately how)  the interaction of host and virus genetics influences HSV pathobiology. We find that the range of virulence displayed by CIs was similar to that seen in commonly employed laboratory isolates, avirulent (e.g. CI 1 and 10 resemble KOS and ANG), moderately virulent (CI 4, 5 and 13 resemble 17Syn+ and SC16), and very virulent (CI 2 and 3 resemble McKrae- arguments about what a “real” wild type phenotype are no longer relevant).  We report here for the first time that the reactivation phenotypes of HSV-1 are dependent on the underlying host genetic background.  Viral isolates that display a low reactivation phenotype in some BXD strains exhibit a high reactivation phenotype in others.  We hypothesize that the diversity observed in clinical viral isolates is the result of evolutionary pressure maximizing transmission in hosts of diverse resistance backgrounds.  Preliminary studies suggest that it will be possible to identify both viral and host genetic factors that regulate such diverse and complex phenotypes as stromal keratitis, virulence, LAT promoter expression and the establishment of and reactivation from latency with this system. 
Mon, March 18, 2013
04:00 PM - 05:00 PM

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