Grant: Master's Award: Canada Graduate Scholarships

The World Health Organization (2009) estimates that 33 million people have died from Human Immunodeficiency Virus (HIV) since its discovery in 1981. Infection with HIV generates an immune response that contains the virus but never eliminates it. Therapeutic vaccines modulate the ongoing immune response in unresolved conditions. In therapeutic cancer vaccines, heteroclitic peptides significantly augment cell-mediated immunity against tumour-associated antigens. Heteroclitic peptides are sequence variants with enhanced functional activity relative to index peptides. We propose that such peptides can also selectively augment interleukin-2 (IL-2) production by HIV-specific CD8+ T cells, which are associated with control of HIV replication and disease progression. Index peptide sequences that stimulate IL-2 production by HIV-specific CD8+ T cells will be identified by ELISpot assays, which identify and enumerate cytokine-producing cells at the single cell level. Potentially heteroclitic variants will be generated by systematic variation of positions 3, 5 and 7 within the index 9mers. Peptide variants that elicit an enhanced response will be selected for Cr51 release assays to estimate the avidity of T cell receptor (TCR)/peptide interactions and flow cytometry analyses to analyze peptide-induced proliferation of CD8+ T cells. Heteroclitic peptides with increased TCR/peptide interaction avidity, relative to the index peptides, could selectively augment IL-2 production and enhance both proliferation and differentiation of HIV-specific CD8+ T cells. If so, they should be incorporated into therapeutic HIV vaccines. Effective therapeutic HIV vaccines potentially offer substantial advantages over antiretroviral therapy including lasting effects following a single administration, reduced short and long term side effects and lower cost. These advantages would greatly improve the quality of life of HIV-infected individuals in both the developed and developing worlds.