A mechanistic investigation of T cell receptor-mediated HIV control

Author: 
Date created: 
2019-09-24
Identifier: 
etd20544
Keywords: 
HIV
Viral control
CD8 T cell
T cell receptor
Vaccine
Human Leukocyte Antigen
Abstract: 

HIV remains a global pandemic. No vaccine or cure exists. Most infected individuals progress to AIDS in the absence of antiretroviral therapy, but a rare group of elite controllers (<0.5% of the infected population) suppresses viremia to an undetectable level. HIV control is often associated with a robust host immune response, mediated by selected HLA alleles that elicit T cells against more conserved HIV peptide epitopes. T cell recognition of an infected cell is determined by its unique T cell receptor (TCR), which binds a virus-derived peptide presented on the cell surface by an HLA protein. An individual’s repertoire of TCR clones is large, but finite, and varies even among those who express the same HLA alleles. TCR sequence differences between controllers and non-controllers have been associated with variation in the antiviral activity of T cells, but few studies have explored this question comprehensively. My thesis project aims to identify TCR features that contribute to HIV control. To do this, I examined CD8+ T cell responses against the immunodominant HIV Gag TL9 (TPQDLNTML) epitope. TL9 is presented by HLA-B*42 and B*81, but only B*81 is associated with HIV control. I sequenced TCR from TL9-specific T cells, including dual-reactive cells associated with HIV control in B*42 individuals that recognized TL9 presented by both B*42 and B*81, and then conducted functional and structural assessments of selected TCR clones. TL9-specific TCR from B*81 individuals and dual-reactive TCR from B*42 individuals were highly enriched for TRBV12-3 gene usage. Furthermore, dual-reactive TCR from B*42 individuals were dominated by shared (or public) clones. Comprehensive functional analyses revealed that TCR from B*81 individuals and dual-reactive TCR from B*42 individuals displayed greater capacity to recognize TL9 variants, including common HIV escape mutations. Structural analyses of two dual-reactive TCR clones demonstrated an unusual peptide binding conformation driven by TRBV12-3 germline residues. My results demonstrate that clonal differences in the ability of TCR to recognize TL9 variants are associated with HIV control. Functional and structural data provide mechanistic insight into key features of more effective TL9-specific TCR. By highlighting the impact of TCR clonotype on HIV control, my results will inform development of new vaccine and therapeutic strategies.

Document type: 
Thesis
Rights: 
This thesis may be printed or downloaded for non-commercial research and scholarly purposes. Copyright remains with the author.
File(s): 
Senior supervisor: 
Mark Brockman
Department: 
Science: Department of Molecular Biology and Biochemistry
Thesis type: 
(Thesis) Ph.D.
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