Identification of neutralising determinants in protection against HIV-1

Hassall, Mark (2010). Identification of neutralising determinants in protection against HIV-1. PhD thesis The Open University.



The main aim of this thesis is the characterisation and understanding of anti HIV-1 responses elicited by vaccination with HIV-1 envelope based vaccines. Initially, the specificity of anti HIV-1 envelope antibodies, elicited by vaccination with an HIV-1 envelope vaccine formulation that has been studied in Phase 1 clinical trials and has been demonstrated to be able to protect macaques against challenge, were determined. In particular, studies were focussed to understand whether the superior neutralising antibody responses that were detected following increasing numbers of vaccinations correlated with qualitative or purely quantitative changes in serological responses. The increase in neutralising ability was observed to be an overall maturation effect of the specificity and avidity of the response. The only correlate found for the incidence of viral breakthrough was a reduced specific V3 epitope response as measured by competition to a V3 crown loop peptide mAb. - 447-52D.

Subsequent topics of research were focussed on evaluation of serological responses generated by HIV-1 envelope immunogens of other clades. The goal of this work was to increase our understanding of HIV-1 isolates as serotypes rather than genotypes. It was found that with the select individual proteins from 5 clades utilised in this work, there were no matching serotypes that could be identified. Indeed the variance in responses from animals having received the same immunogen formula was in some cases quite marked, for both binding and neutralising specificity.

Initial work to investigate cross reactivity of binding antibody and neutralising responses was expanded to analyse serological responses to C clade immunogens by the production and characterisation of novel murine monoclonal antibodies. The successful production of novel anti C-clade monoclonal antibodies was somewhat tempered by the lack of induced neutralising ability of any of these. However these materials will still provide valuable reagents for further research into what is the most prominent clade of the virus worldwide.

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