Solache-Diaz, Maria Emma Alejandra; (1998) Selection of CMV-specific HLA-A2 restricted cytotoxic T lymphocytes using peptides from the CMV protein pp65. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The cytotoxic T lymphocyte (CTL) response to cytomegalovirus (CMV) is thought to play an important role in defence against this virus, and in those with compromised T cell immunity CMV is an important pathogen. Analysis of the antigen specificity of the CMV-specific CTL response has shown that it is directed almost entirely to a single tegument protein, the phosphoprotein pp65. The present study aimed to determine the nature of the CTL response to this CMV protein in the context of the HLA-A*0201 antigen.Screening of the protein sequence of pp65 revealed 17 peptides which fulfilled the anchor binding motif requirements for HLA-A*0201. The binding affinity of these peptides to the HLA-A*0201 antigen was assessed using two methods. The peptides shown to bind were then assayed for the ability to induce an HLA-A*0201 restricted CTL response in vitro. Three epitopes were identified which stimulated in vitro CTL responses from the peripheral blood lymphocytes of CMV seropositive individuals. Such peptide-specific CTLs also recognised the naturally processed pp65 presented either in CMV infected cells, or in cells infected with an adenovirus construct expressing this protein. The three CTL epitopes identified were conserved in four clinical isolates and three laboratory strains of CMV.The identification of these pp65 immunogenic epitopes may provide a useful basis for the development of future CMV immunotherapies, which could serve to generate a primary CTL response to CMV in seronegative individuals, or to amplify a memory CTL response in seropositive individuals. In the design of a potential peptide vaccine the ideal situation would be to target as high a number of the affected population as possible, and thus pp65 CTL epitopes for other HLA antigens need to be identified. The latter could be achieved using the strategy successfully employed in the present study for the HLA-A*0201 antigen.

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