MHC Loci in the Control of Marek's Lymphoma

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DESCRIPTION (provided by applicant): Oncogenic herpes viruses drive most cancers associated with HIV infection and other immunosuppressed conditions. The close association between immunity and tumor growth in these cancers is obvious. Relief of immunosuppression can bring cancer remission. Over time complex interactions have evolved between oncogenic virus, tumor and vertebrate host. The Marek's disease (MD) virus in the chicken provides useful model for learning more about the role of vertebrate genetics in controlling tumor growth caused by herpes virus transformation. Particular major histocompatibility complex (MHC) haplotypes in the chicken have strikingly strong roles in suppressing the growth of MD lymphomas, while other MHC haplotypes provide moderate or no protection. Two ostensibly identical recombinant MHC haplotypes were shown in earlier studies to differ in response to MD tumors. In preliminary work we have demonstrated that, although identical at class I, class II and a cluster of BG loci, the two recombinant haplotypes differ in crossover breakpoints within a restricted region in the vicinity of a distinctive BG locus that has intriguing features and is likely involved in signaling. In addition to the unusual BG locus there is a putative NK-cell receptor gene posited as important in controlling tumor growth (surrounded by long-inverted repeats that are typical of DNA predisposed to instability and increased homologous recombination in adjacent regions). We seek to 1) confirm the difference between the two recombinant haplotypes, BR2 and BR4 in response to challenge with MD virus and extend the test to include a third closely related recombinant haplotype BR3 using fully congenic strains now available in additional MDV challenge trials; 2) define the allelic differences at the candidate loci in BR2-BR4 recombinant haplotypes and haplotypes conferring high resistance and high susceptibility to MD tumors by resequencing the interval surrounding the crossover breakpoints; and 3) study the constitutive expression of candidate loci in organs associated with MDV infection and profile changes which occur in these and other loci during the course of viral infection and tumor formation in birds that bear the different MHC haplotypes and differ in tumor growth following infection.