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In Vitro Investigation of the Role of Human Cytomegalovirus Glycoprotein Polymorphisms in Disease Pathogenesis

Abdulhakim, Jawaher Abdulbaqi D

[Thesis]. Manchester, UK: The University of Manchester; 2018.

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Abstract

HCMV is a common viral pathogen that infects most of the world's population by early adulthood. It is typically asymptomatic in immunologically healthy individuals but causes severe disease in immunocompromised patients and congenitally infected infants. HCMV glycoproteins are highly polymorphic, and various types of associations have been suggested between glycoprotein types and the pathogenicity of the virus. Several studies on viruses other than HCMV have related the glycosylation of the viral glycoproteins to virulence. This project aimed to determine whether there is a robust relationship between the individual glycoprotein sequence and its glycosylation, how this influences the growth characteristic of the virus and whether this is related to its pathogenicity. Glycosylation patterns of 89 clinical specimens of different infection categories and specimen types were correlated with genetic sequence alterations of the virus glycoproteins (gB, gH, gL, gM, gN, gO), followed by determining whether mutation results in specific changes in glycosylation. The aim was approached using a cell culture model and a quantitative lectin-based assay (ELLA). A significantly increased glycosylation level for the following genotypes: mixed gH, gN4a, gO4, mixed gL was detected. Whereas a decreased pattern was found to be associated with gH1, gH2, gN3a, gO1a and gL2 genotypes (P<0.05). Glycoproteins of strains isolated from respiratory specimens were significantly highly glycosylated compared to the blood and urine samples, and from blood specimens compared to the urine samples (P<0.05). Furthermore, strains from congenitally infected infants and urine samples had a significantly higher growth rate than others tested. No direct association between the virus growth and its virulence was found. These findings demonstrate that glycosylation of glycoproteins in HCMV is affected by the glycoprotein polymorphisms and signifies a potentially important mechanism for avoidance of antibody-mediated neutralization, which, in turn, facilitates HCMV pathogenicity. This phenomenon requires further study and may have application for the selection of novel targets for diagnosis, vaccine development and other preventive measures to combat diseases caused by this virus.