Characterization of the Mamu-A*01-Restricted CD8-Positive T Lymphocyte Immunodominance Hierarchy in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

• Main Author: Osuna-Gutierrez, Christa Elyse
• Other Authors: Letvin, Norman
• Language: en_US
• Published: Harvard University 2012
• Subjects: CD8 T cell; differentiation; HIV; SIV; T cell receptor; vaccine; immunology; molecular biology; virology
• Online Access: http://dissertations.umi.com/gsas.harvard:10600; http://nrs.harvard.edu/urn-3:HUL.InstRepos:9817660

\(CD8^+\) cytotoxic T lymphocytes (CTLs) play a critical role in controlling human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. The CTL responses that are thought to be the most protective against HIV and SIV are those that are of high frequency, recognize multiple epitopes, and perform multiple antiviral functions. Therefore, current vaccines aim to elicit CTLs possessing these characteristics. However, the phenomenon of immunodominance likely limits the potential of vaccines from generating such CTL responses by restricting the breadth of epitopes recognized by CTLs and the frequency and functionality of these CTL responses. In this dissertation, we explored the relationship between SIV epitope dominance and the functionality of the epitope-specific CTL populations. We also examined factors that contribute to the development of SIV epitope immunodominance hierarchies. We initially investigated the relationship between SIV epitope dominance and the antiviral functionality of the epitope-specific CTL populations in rhesus monkeys. We performed a gene expression analysis in dominant and subdominant epitope-specific CTLs during the acute phase of SIV infection and observed differential expression of a number of genes during this time. Subsequent in vitro functional studies of these epitope-specific CTL populations during the chronic phase of infection confirmed the presence of differences in maturation phenotype and functional capacity of dominant and subdominant epitope-specific CTLs. These studies demonstrate a relationship between epitope dominance and antiviral functionality of epitopespecific CTLs and suggest that dominant and subdominant epitope-specific CTLs may differ in their protective role against HIV acquisition and replication. This has important implications for vaccine design. In subsequent studies, we investigated the contribution of the binding of the peptide:MHC (pMHC) complex to the T cell receptor (TCR) in the development of immunodominance hierarchies. Using surface plasmon resonance, we measured the kinetics and the affinity of the interactions between dominant and subdominant epitope pMHC complexes with their respective TCRs. We found that epitope dominance was associated with higher affinities of pMHC:TCR binding. These findings indicate a molecular interaction that may be manipulated in vaccine-induced CTL responses to enhance their frequency and functional capacity.