Modulating the Immune Response to the Gag P24(19-27) Epitope TV9

The global HIV epidemic continues to expand despite more than 15 years of intensive research and clinical trials. The best hope to stop the continuing spread of HIV worldwide is an effective vaccine; this however is proving to be an unprecedented scientific challenge. The goal of this thesis was to characterize the human T cell repertoire to the subdominant Gag p2419-27 epitope, TV9 (TLNAWVKVV), to ascertain its potential usefulness as a component of an HIV-1 vaccine. While this response is relatively silent in Western cultures, this epitope has been purported to play a protective role in African sex workers. To exclude the possibility that the paucity of reactivity to TV9 in patients was due to lack of a human CD8+ T cell repertoire for this epitope, we attempted to prime TV9-specific T cells (TV9-CTLs) ex vivo from healthy seronegative donors. Through ex vivo priming studies we were able to show that TV9-specific T cells could be primed from circulating CD8+ T cells of healthy individuals. Further, we found that the human T cell repertoire to TV9 was clonally diverse and that a dominant clonotype(s) did not emerge over time. This finding may explain why TV9 is a subdominant epitope (not prominent in patients). We next examined whether the TV9 response could be further enhanced through the use of altered peptide ligands. Using TV9-CTLs to scan a synthetic combinatorial nonameric peptide library we were able to identify a panel of 48 potential altered peptides ligands (or mimics). Of these, the TV9 mimic p6 was shown to consistently elicit TV9-crossreacitve CTLs. Moreover we found that p6-CTLs were more efficient at lysing HIV-1 infected target cells. This study supports the notion that the TV9-CTL repertoire is complex and sustainable. Further, defining the T cell repertoires to TV9 and related peptides may help us to understand why these responses do not control infection and may also provide insights into how we might enhance these responses. Ultimately the exploitation of TCR degeneracy in the response to TV9 and identification of agonist mimics such as p6 may lead to improvement in the design of HIV-1 vaccines.