Lankina, Anastasia; (2024) Interdisciplinary analysis of human cytomegalovirus glycoprotein B function, antigenicity, and conservation across herpesviruses. Doctoral thesis (Ph.D), UCL (University College London).

Text Anastasia_Lankina_thesis_corrected.pdf - Accepted Version Access restricted to UCL open access staff until 1 January 2026. Download (25MB)

Abstract

Human cytomegalovirus (HCMV) is a major cause of morbidity in immunodeficient populations and is the leading viral cause of congenital disease which manifests mainly as neurological impairments in neonates. Development of an effective vaccine against HCMV remains the highest priority. While no licensed vaccine exists currently, a vaccine candidate based on the virion envelope constituent glycoprotein B (gB) fusogen has shown the highest level of efficacy so far. Here I present an interdisciplinary analysis of gB function and properties with a focus on regions important for effective anti-gB immune responses. First, I interrogated the recently discovered antigenic domain 6 (AD-6) and demonstrated that AD-6 structure, but not sequence, is highly conserved across other herpesviral gB proteins arguing for a common, structure-related, function of AD-6. Consistent with this, a polyclonal antibody raised against HCMV AD-6 was effective at reducing the spread of two other herpesviruses. Next, I investigated AD-2 which contains a linear epitope targeted by neutralising antibodies. In contrast to the conserved sequence of this epitope, AD-2 upstream sequence is highly variable. A sequence analysis suggests that the AD-2 variation across HCMV strains could introduce changes to glycosylation patterns near the neutralising epitope. Moreover, a binding assay was able to confirm that deglycosylation of whole HCMV virions leads to an increase in AD-2-specific antibody binding, outlining the potential contribution of glycan shielding to the viral strategies of antibody evasion. Finally, a systematic analysis of vaccine-induced immune responses revealed a short region of a larger antigenic domain, AD-5, a response to which was shown to contribute to the neutralising ability of vaccine recipient sera. Thus, this thesis presents a combination of in silico and in vitro approaches and aims to enhance the understanding of molecular and immunological properties of gB with potential to advance HCMV vaccine development.

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