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Title page for ETD etd-04292011-141143


Type of Document Dissertation
Author Conrad, Joseph Allen
Author's Email Address joseph.a.conrad@vanderbilt.edu
URN etd-04292011-141143
Title Clonotypic Dominance within the HIV-epitope-specific T cell receptor repertoire correlates with phenotypic and functional impairment
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Sebastian Joyce, Ph.D. Committee Chair
Geraldine Miller, MD Committee Member
James Crowe, MD Committee Member
Julian Hillyer, Ph.D. Committee Member
Spyros Kalams, MD Committee Member
Keywords
  • TCR
  • HIV
  • T cell
  • CTL
Date of Defense 2011-04-14
Availability unrestricted
Abstract
HIV-epitope-specific T cell responses are critical components of the natural immune response to HIV infection, but these cells often become dysfunctional in chronic infection. Structural diversity within the epitope-specific T cell receptor (TCR) repertoire is likely beneficial in the suppression of viral epitope variants. However, the relationship between the structural and clonotypic composition of the HIV-specific TCR repertoire, clonotypic surface and functional phenotype, and avidity for and exposure to antigen is poorly defined. Dominant and sub-dominant epitope-specific T cell clonotypes were identified and the TCR repertoire was assessed over time. Surface expression of PD-1, CD38, CD127, CD45RO, and CCR7 was measured and used to define exhaustion and memory profiles on epitope-specific T cell populations during chronic infection and after initiation of antiretroviral therapy. Dominant clonotypes in chronic infection express a surface phenotype consistent with exhaustion which is unchanged after narrowing of the repertoire following initiation of antiretroviral therapy. Despite their cell surface phenotype, dominant clonotypes were capable of cytokine production and proliferation when stimulated with peptide epitopes, but sub-dominant clonotypes produced higher relative levels of cytokines and displayed greater variant cross-recognition compared to corresponding dominant clonotypes. Together, these data indicate that dominant clonotypes within HIV-specific T cell responses display a phenotype consistent with ongoing exposure to cognate viral epitopes, that TCR repertoire diversity may be maintained by antigen exposure, and suggest that cross-reactive, sub-dominant clonotypes may retain greater capacity to suppress replication of viral variants. Overall, these findings impact our understanding of how the TCR repertoire is maintained in HIV and provide insight into the potential effects of future immunomodulatory therapies.
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