Manuel, Donna Marie; (1996) Analysis of sequence variation of human cytomegalovirus envelope glycoproteins and consequences for recognition by neutralising antibodies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

HCMV is a virus which establishes lifelong persistence in its host. In the face of an immune response, reinfection and reactivation may still occur which may be due in part to sequence heterogeneity amongst different strains in proteins involved in viral infectivity. The objectives of this thesis were to perform a comprehensive sequence analysis of neutralising determinants of HCMV amongst clinical isolates, and to determine the biological consequences of virus strains having variant sequences. The nucleotide sequences for regions containing neutralizing determinants within the envelope glycoproteins gB and gH were determined for a large number of clinical HCMV strains from AIDS patients and renal transplant recipients. A comprehensive phylogenetic analysis of sequence data for each region was performed and revealed that clinical HCMV strains segregated into a limited number of subtypes at each site. The segregation was also region dependent, with the suggestion of recombination events not only between the gH and gB loci, but also within the gB locus at two different genetic sites. Analogous results were obtained for the amino acid sequences translated from nucleotide sequence data. Thus, it may be necessary to include components from a number of prototype HCMV strains when formulating a subunit vaccine. Concatenation of sequence data, followed by phylogenetic analysis served to provide a unique identity for HCMV strains, and characterise relationships between subtypes. Such data might be useful where correlations are made between virus subtype and the pathogenesis of virus infection. Functional analyses were performed with variant virus strains to determine the biological implications of mutations observed within neutralising determinants of HCMV. The reactivity of a panel of monoclonal antibodies and human sera was markedly altered against a number of the variant strains, and in one case neutralising activity of antibodies was enhanced by mutations. These findings suggest that strain specific differences may contribute to the pathogenicity of HCMV, and it is therefore important to consider sequence heterogeneity within neutralising determinants of the envelope glycoproteins of HCMV when designing subunit vaccines or therapeutic agents such as human monoclonal antibodies.

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