Genetic Modifiers of Immune Evasion by Cytomegalovirus in Glioblastoma

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DESCRIPTION (provided by applicant): Increasing evidence implicates human cytomegalovirus (HCMV) in the etiology of glioblastoma (GBM): HCMV proteins have been implicated as tumor promoters in gliomagenesis; glioma grade-as well as patient survival-directly correlates with the level of HCMV gene products. In this proposal, we seek to understand why this common herpesvirus causes disease in only a subset of those infected: HCMV seroprevalence, 80% vs. the prevalence of GBM, 0.025%. HCMV has evolved highly sophisticated immune evasion strategies. One strategy involves generating two proteins-encoded by genes TRL11/IRL11 and UL119-UL118-that have functional properties of the Fc?R, which may enable the virus to evade host immunosurveillance by evading the effector consequences of antibody binding, such as ADCC. Recent studies from our laboratory show that alleles of a major gene complex of the immune system-GM allotypes encoded by three highly polymorphic IGHG loci on chromosome 14-modulate this viral strategy: The HCMV TRL11/IRL11-encoded Fc?R has significantly higher affinity for IgG1 proteins expressing the GM 3+,1-,2- allotypes than for those expressing the allelic GM 17+,1+,2+ allotypes (p = 0.0005). These observations led us to hypothesize that GM genes are effect modifiers of HCMV-GBM association and the underlying mechanisms include their contribution to anti-HCMV antibody responses and their modulating influence on the viral immune-evasion strategies. The following specific aims will test our hypothesis: 1) Determine if the distribution of GM determinants in GBM patients is different from that in controls. DNA from GBM patients and controls will be genotyped for several GM alleles. Because of their higher affinity to the HCMV-encoded Fc?R, anti-HCMV IgG1 antibodies expressing the GM 3+,1-,2- allotypes would be more likely to have their Fc domains scavenged, thereby reducing their immunological competence to eliminate the virus through ADCC and other Fc-mediated effector mechanisms. Consequently, the frequency of these allotypes would be expected to be higher in patients than in controls; 2) Compare the levels of anti-HCMV antibodies in GBM patients and in controls, and determine if they are associated with particular GM alleles. Antibodies to HCMV glycoprotein B (gB) in the sera/plasma of patients and controls will be quantitated by an ELISA and the levels will be compared between the two groups. We will also determine whether the antibody levels are associated with particular GM alleles; 3) Determine if HCMV-encoded Fc?R proteins bind differentially with genetically disparate Fc (GM) regions of anti-HCMV IgG antibodies in GBM patients. Ectodomains of HCMV-encoded Fc?Rs will be cloned and expressed. We will purify IgG antibodies directed against HCMV gB from the sera of GBM patients. Binding and comparative affinities of IgG molecules of different GM allotypes to the HCMV Fc?Rs will be monitored by surface plasmon resonance. Results from the proposed investigation are likely to open a new avenue of investigation in a malignancy that kills approximately 13000 people every year in the U.S. alone.