Year of Award

2020

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Biochemistry & Biophysics

Department or School/College

Division of Biological Sciences

Committee Chair

Ekaterina Voronina

Commitee Members

Brent Ryckman, Stephen Lodmell, Bruce Bowler, Mark Grimes, Ekaterina Voronina

Keywords

cytomegalovirus, glycoproteins, genetic diversity, antibody neutralization, tropism, spread

Publisher

University of Montana

Subject Categories

Biochemistry | Cell Biology | Molecular Biology | Virology

Abstract

Human cytomegalovirus (HCMV) is widely spread throughout the world and immunocompromised individuals can suffer severe diseases from HCMV infection. Once the infection is established, HCMV can spread through the body and infect many major somatic cell types. The glycoproteins H and L (gH/gL) on HCMV envelope can be bound by either gO or the UL128-131 proteins to form complexes gH/gL/gO and gH/gL/UL128-131 that are critical for viral entry and spread, and these two complexes are important targets of neutralizing antibodies. Strains of HCMV vary considerably in the levels of gH/gL/gO and gH/gL/UL128-131. gO is one of the most diverse loci among strains with 10-30% of amino acid sequence differences. In this thesis I explored the mechanisms behind the complex assembly differences between strains and the impacts of interstrain gO diversity on the biology of HCMV. My results uncovered that the strain variations in the assembly of gH/gL complexes is due to the differences in the expression level of gO and UL128-131, while gO amino acid sequence differences have no influence on the complexes assembly. Interestingly, the diversity of gO has dramatic impacts on HCMV cell-free and cell-to-cell spread as well as on antibody neutralization and these effects of gO polymorphisms are epistatically dependent on other variable loci in the virus genome. My study could help to understand the complexity of genotypes observed in clinical samples and decode the challenge for intervention approaches against HCMV.

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© Copyright 2020 Le Z. Day