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Wu, Yi-Quan (2017): The role of the cytomegalovirus glycoprotein complex gHgLgO in virus entry. Dissertation, LMU München: Medizinische Fakultät
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Wu_Yi-Quan.pdf

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Abstract

Human cytomegalovirus (HCMV) infection is a major cause of morbidity and mortality in immunocompromised individuals and a leading cause of birth defects after congenital infection. Herpesvirus cell tropism is determined by gH/gL glycoprotein complexes in the viral envelope. The gH/gL complexes mediate virus entry into host cells through binding to host cell receptors and promote fusion of viral envelopes with cellular membranes. HCMV encodes two alternative gH/gL complexes, gH/gL/gO and gH/gL/pUL (128, 130, 131a) which both shape the broad cell tropism of HCMV. However, their respective host cell receptors have not been identified. HCMV shows a broad cell tropism and readily produces infectious supernatant virus in cell culture. HCMV lacking the gH/gL/gO complex hardly produces infectious virus and spreads mainly cell-associated. By studying the binding of HCMV particles and recombinant gO-IgG Fc fusion proteins to fibroblasts, platelet-derived growth factor receptor-α (PDGFRα) could be identified as an HCMV entry receptor recognized by the gH/gL/gO complex. It could be shown that only gH/gL/gO-positive HCMV infects cells in a PDGFRα-dependent manner: i) Soluble PDGFRα receptor and the natural ligand PDGF-BB could inhibit infection with wildtype virus, but not infection with gO-knockout mutants. ii) Overexpression of PDGFRα enhanced infection with wildtype virus, but not infection with gO-knockout virus. It could also be shown that infection of PDGFRα-positive cells is up to 98% driven by the gH/gL/gO complex. This might indicate that, PDGFRα expression levels secure effective infection of first target cells. The PDGFRα - gH/gL/gO interaction may thus be an important target for the design of anti-HCMV vaccines or new anti-HCMV drugs to prevent primary infection. Infection of mice with murine cytomegalovirus (MCMV) has been extensively used as a model to study HCMV infection in vivo. It has been shown before that MCMV also expresses a gH/gL/gO complex which, when knocked out, exhibits a phenotype in cell culture comparable to gO-knockout mutants of HCMV. Here, it could be shown that gOknockout mutants of MCMV and HCMV show similar shifts in infection capacities for different cell types. MCMV progenies derived from different cell types differ like HCMV progenies derived from different cell types in their cell tropism. This is very likely due to cell type-dependent incorporation of more or less gH/gL/gO complexes. This makes the MCMV infection of mice a good model to study the role of the gH/gL/gO complex in vivo.