All ETDs from UAB

Advisory Committee Chair

Paul A Goepfert

Advisory Committee Members

Laurie Harrington

Christina Ochsenbauer

Hubert M Tse

Amy Weinmann

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Since the 1980s, HIV infection has caused millions of death and tremendous economic losses worldwide. Despite great scientific advances, the only effective therapy to date, antiretroviral therapy (ART), merely delays disease progression yet cannot eradicate viral infection. Therefore, an effective HIV vaccine that can prevent the acquisition of infection would be a desirable alternative. The critical role of CD8 T-cell immunity in HIV infection has been well documented and therefore not surprisingly a great deal of effort has been focused on developing an effective CD8 T-cell based HIV vaccine. However, by far, such CD8 T-cell based HIV vaccine trials have been shown with disappointing clinical outcomes among human recipients. A major obstacle that likely accounts for vaccine failure lies in the enormous genetic diversity of HIV. This retrovirus frequently adapts to CD8 T-cell responses, leading to the preferential accumulation of escape mutations in the viral genome. The work presented in this dissertation examined the impact of human leukocyte antigen class I (HLA-I) associated adaptation on CD8 T-cell responses and their biological relevance in HIV infection and vaccination. Our results show that the immunogenicity of viral epitopes harboring adaptations or escape mutations (adapted epitopes) increased following acute HIV infection. Despite enhanced T-cell recognition in chronic HIV infection, viral sequencing identified HIV strains encoding numerous adapted epitopes as the dominant circulating viruses. Using single cell RNA sequencing, we found CD8 T cells targeting adapted epitopes exhibited a unique transcriptomic signature reflecting lower polyfunctionality and proliferative capacity. In addition, these CD8 T cells also promoted higher levels of dendritic cell (DC) maturation than those that targeted non-adapted epitopes, resulting in higher HIV trans-infection from DCs to CD4 T cells among both chronically HIV infected individuals and vaccine recipients in a T cell based vaccine trial, the MRKAd5. Moreover, in analyzing the rate of HIV infection in MRKAd5 trial participants, we observed that vaccine recipients in whom the immunogen encoded a high number of epitopes that were adapted with respect to their respective HLA-I allelic repertoire were more susceptible to HIV infection. In conclusion, our work challenges the prevailing paradigm that viral adaptations confer an evolutionary advantage by merely impairing CD8 T-cell recognition and demonstrates the presence of alternative adaptation strategies other than classical immune escape. We believe that this study provides a novel perspective of how HIV benefits from adaptation and offers important considerations for immunogen selection for designing an effective T-cell based vaccine.

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