Breadth and Functional Assessment of "Toggle"-Peptide-specific T Cell Responses

Massachusetts General Hospital, Boston MA

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Abstract

HIV sequence diversity is a major hurdle for the development of an HIV vaccine and severely impacts the ability to detect ex vivo immune responses in HIV infected individuals. Different approaches have been suggested to cope with this issue, but have not always been effective in overcoming the discrepancy between infecting viral sequence and in vitro antigen test sets. As a consequence, most immune analyses to date provide limited information on the immunogenicity of sequence variants that could represent valuable candidates for HIV vaccine design. In addition, most past efforts defining immune correlates of controlled HIV infection have been similarly limited in their inclusion of sequence diversity, questioning whether all of the phenotypic and functional characteristics of reportedly protective responses would extend to variant sequences. The use of "toggled" peptides, representing essentially small peptide libraries with limited diversity, has the potential to overcome a number of these problems, providing important guidance for antigen selection and sequence variant inclusion in future vaccine immunogens. Aside from detecting significantly more and stronger HIV-specific immune responses, sequence variants that are present in the toggled peptides may induce quantitatively and qualitatively different immune responses, for both CD4 as well as CDS T cells, providing the basis to more comprehensively define potential immune correlates of controlled HIV infection. Based on extensive preliminary data showing the superiority of toggled peptides to elicit T cell responses compared to different single sequence (e.g. consensus) test reagents, the present application aims in a first step to define the level of sequence diversity coverage that provides optimal detection of HIV-specific responses in a cohort of HIV clade B infected individuals with varying disease control. Subsequently, toggled peptides are investigated for their ability to stimulate recall responses with different functional and phenotypic patterns, identifying sequence variants with improved immunogenicity and associated with polyfunctional responses. The frequency of these sequence variants in the HIV database and the preferential detection of specific polyfunctional response patterns in HIV controllers will be investigated to support rational sequence variant selection for inclusion in vaccine candidates. Overall, the proposed studies will provide urgently needed information on the impact of sequence diversity on the functional properties of virus-specific CD4 and CDS T cells, and together with an assessment of the potential for T cell responses to cross-react between different viral isolates or clades, the analyses will support the further design of HIV vaccines immunogens that can induce broad, strong and self-renewing T cell responses with wide cross-reactivity potential.