Eliciting protective immune responses to HIV with vaccines requires the generation of long-term cellular and humoral immunity. Characterizing HIV-specific vaccine-induced responses has led to interesting findings regarding CD8+ T cell and CD4+ Th1 differentiation, functionality, memory persistence and clonal architecture. However, immune correlates of protection in HIV are still not well characterized. Differing functional and phenotypic characteristics in cellular immune responses have been reported with respect to a variety of vaccine strategies. In addition, several studies have described the clonal nature of the CD8+ T cell response after vaccination. It is of interest to reconcile the functional, phenotypic and clonal nature of the CD8+ T cell response after vaccination using different vaccine strategies in an attempt to eluicidate protective responses in HIV. In this study, using polychromatic flow cytometry and clonotypic analysis, we examined how antigen dose affects vaccine-induced CD8+ T cell responses to Gag65-73 AI9 (AMQMLKETI) and Pol76-84 LI9 (LVGPTPVNI) in a mouse model of a replication incompetent adenoviral vaccine modality. The results showed that low dose vaccination generates the most desired functional and clonal response to Gag 65-73 AI9 suggestive of a protective response especially at acute time points after vaccination. CD8+ T cell responses to Gag65-73 AI9 after low dose vaccination were polyfunctional, polyclonal, lacking preferential variable and joining gene usage in the T cell receptor beta chain (TCRBV and TCRBJ), and lacked any amino acid sequence motif. In contrast, the CD8+ T cell response to Pol76-84 LI9 was polyfunctional and polyclonal; however, T cell receptor beta chains exhibited a preferential usage of TCRBV16 and TCRBJ2-5 and an amino acid sequence motif of CASSLxGGxQDTQYF. These results suggest that comprehensive study of the interplay between CD8+ T cell functionality and clonality may provide more information to aid in the design of an effective vaccine to HIV.
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|Advisor:||Douek, Daniel C., Johnson, Diana|
|Commitee:||Constant, Stephanie, Davidson, Wendy, Schwartzberg, Pamela, Seder, Robert|
|School:||The George Washington University|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 71/01, Dissertation Abstracts International|
|Keywords:||CD8+ T cells, Clonotypes, HIV, Polyfunctionality, Vaccines|
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